Trial Title: Internal Reference Number / Short title ...

Date and version No: 30.12.2020 version 6.3

TM101-C Protocol Template for Clinical Trial version 15.0 CONFIDENTIAL © Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2019 of 66

Trial Title: Platform Randomised trial of INterventions against COVID-19 In older peoPLE Internal Reference Number / Short title: PRINCIPLE

Ethics Ref: 20/SC/0158 IRAS Project ID: 281958

EudraCT Number: 2020-001209-22 Date and Version No: 30th December 2020 version 6.3

Chief Investigator and trial leader:

Professor Chris Butler, Department of Primary Care Health Sciences University of Oxford

Co-Principal Investigator and Co-trial lead:

Prof Richard Hobbs, Department of Primary Care Health Sciences University of Oxford

Co-Principal Investigators:

Prof Simon de Lusignan, RCGP Research Surveillance Centre, University of Oxford Prof Gail Hayward, Department of Primary Care Health Sciences University of Oxford

Investigators: Dr Ly-Mee Yu, Primary Care Clinical Trials Unit, Department of Primary Care Health Sciences, University of Oxford

Dr Emma Ogburn, Primary Care Clinical Trials Unit, Department of Primary Care Health Sciences, University of Oxford

Dr Oliver Van Hecke, Department of Primary Care Health Sciences, University of Oxford

Ms Julie Allen, Primary Care Clinical Trials Unit, Department of Primary Care Health Sciences, University of Oxford

Dr Emily Bongard, Primary Care Clinical Trials Unit, Department of Primary Care Health Sciences, University of Oxford

Dr Hannah Swayze, Primary Care Clinical Trials Unit, Department of Primary Care Health Sciences, University of Oxford

Dr Sharon Tonner, Primary Care Clinical Trials Unit, Department of Primary Care Health Sciences, University of Oxford Dr Nina Gobat, Department of Primary Care Health Sciences University of Oxford

Ben Saville, PhD, Berry Consultants, Texas, USA, & Department of Biostatistics, Vanderbilt University School of Medicine, Tennessee, USA

Prof Martin Llewellyn, Professor in Infectious Diseases, Medical Research Building, Room 1.08, BSMS, University of Sussex

Prof Stavros Petrou, Department of Primary Care Health Sciences University of Oxford



Dr Monique Andersson, Oxford University Hospital NHS Trust

Dr Susan Hopkins, Incident Director for COVID-19, Public Health England

Dr Sarah Tonkin Crine, Department of Primary Care Health Sciences, University of Oxford

Dr Aleksandra Borek, Department of Primary Care Health Sciences, University of Oxford

Dr James Ray, Oxford University Hospitals Emergency Medicine Consultant, NHS England Lead for Urgent and Emergency Care for Thames Valley and London

Prof. Mahendra G Patel, Honorary Visiting Professor of Pharmacy University of Bradford , Honorary Senior Lecturer Academic Unit Primary Care Medical School University of Sheffield

Sponsor: University of Oxford Funder: UKRI/NIHR Joint Research Office 1st floor, Boundary Brook House Churchill Drive, Headington Oxford OX3 7GB

Chief Investigator Signature: Statistician Signature:

No potential conflict of interest Confidentiality Statement This document contains confidential information that must not be disclosed to anyone other than the Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics Committee and Regulatory Authorities unless authorised to do so. See supplementary material B for Key Trial Contacts.



Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE): Overview

Background: There is an urgent need to identify effective treatments for SARS-CoV-2 infection, that reduce the need for hospital admission and reduce the time to recovery. We have established an open, adaptive, platform trial to evaluate treatments suitable for use in the community for treating COVID-like-illness that might prevent hospitalisation and/or death and help people recover sooner.

Eligibility and randomisation: This protocol describes a randomised trial for people in the community aged 65 and over, or 50 and over with comorbidity, with possible (in accordance with the United Kingdom’s Chief Medical Officer’s syndromic case definition) or confirmed SARS-CoV-2 infection. Participants are randomised to receive either usual care or a trial treatment (see appendices for details of all trial arms). Participants can take part in the study if they are eligible to be randomised to at least one intervention arm as well as the Usual Care arm. Platform trial: A “platform trial” is a trial in which multiple treatments for the same disease are tested simultaneously. New interventions can be added or replace existing ones during the course of the trial in accordance with pre-specified criteria. Response adaptive randomisation: The initial randomisation ratio is fixed 1:1 for a comparison between two trial arms, but the trial has the capability for these proportions to be altered according to participants’ responses to interventions. Pre-specified decision criteria allow for dropping a treatment for futility, declaring a treatment superior, or adding a new treatment to be tested. If at any point a treatment is deemed superior to the usual care arm, the superior treatment may replace the usual care arm as the new standard of care. In the context of the COVID-19 pandemic, the trial may continue as long as the pandemic persists. Outcomes: The trial has co-primary endpoints: 1) Time taken to self-reported recovery; and 2) hospitalisation and/or death. The main objective of the trial is to assess the effectiveness of the interventions in reducing time to recovery and in reducing the incidence of hospitalisation and/or death.

Key secondary outcomes include: Hospital assessment without admission; Oxygen administration; Intensive Care Unit admission; Mechanical ventilation (components of the WHO Clinical Progression Ordinal Scale); Duration of hospital admission; Duration of severe symptoms; Sustained recovery; Contacts with the health services; Consumption of antibiotics; Effects in those with a positive test for COVID-19 infection; WHO Well-being Index.

See supplementary material C for details of objectives and outcome measures.

Efficient study design: All enrolment (screening, informed consent, eligibility review and baseline data) and follow-up procedures (daily diary, hospitalisations and deaths) can be performed and captured online on the trial website or by telephone with a member of the trial team. Randomisation is online and automatic following eligibility confirmation. Participant packs and medications are sent from the central study team directly to the participant.



Data to be recorded: We will capture demographic features including ethnicity and care home residency at baseline. In the online daily diary (completed for 28 days)/ during telephone calls, participants or their Study Partners will rate the severity of symptoms, record contacts with the health services (including hospital admission), record medication use, and new infections in the household. The WHO-5 Wellbeing Index, a five-question instrument, will assess wellbeing at baseline and on days 14 and 28. Follow-up beyond 28 days after randomisation will be accessing electronic medical records and by participant questionnaire for information relevant to the longer term consequences of COVID-19. Numbers to be randomised: The trial will continue until either superiority or futility is claimed for each intervention. We estimate that approximately 400 participants per arm (800 participants total if only a single intervention vs. Usual Care) will be required to provide 90% power for detecting an approximate difference of 2 days in median recovery time. We estimate that approximately 1500 participants per arm (3000 participants total if only a single intervention vs. usual care) will be required to provide 90% power for detecting a 50% reduction in the relative risk of hospitalisation and/or death.

To enquire about the trial, contact the PRINCIPLE Trial Team:

PRINCIPLE Trial Nuffield Department of Primary Care Health Sciences

Radcliffe Primary Care Radcliffe Observatory Quarter, Woodstock Road

Oxford OX2 6GG

Email Address: [email protected]

Tel: 0800 1385451

Website: www.principletrial.org

mailto:[email protected]

http://www.principletrial.org/



TABLE OF CONTENTS 1. BACKGROUND and RATIONALE........................................................................................ 9

2. TRIAL DESIGN AND PROCEDURES .................................................................................. 9

2.1 Participant Identification ....................................................................................................... 9

2.1.1 Trial Participants .............................................................................................................. 9

2.1.2 Inclusion Criteria ........................................................................................................... 9

2.1.3 Exclusion Criteria ........................................................................................................ 10

2.2 Trial procedures .................................................................................................................. 10

2.2.1 Recruitment .................................................................................................................. 10

2.2.2 Face to face ................................................................................................................... 10

2.2.3 Remote recruitment....................................................................................................... 10

2.3 Screening ......................................................................................................................... 11

2.4 Informed Consent ............................................................................................................ 12

2.5 Eligibility Assessment ..................................................................................................... 13

2.6 Randomisation ...................................................................................................................... 13

2.7 Blinding and code-breaking ............................................................................................ 13

2.8 Baseline Assessments ...................................................................................................... 13

2.9 Subsequent Visits ............................................................................................................ 14

2.10 Qualitative Sub-study ...................................................................................................... 14

2.11 Early Discontinuation/Withdrawal of Participants .......................................................... 15

2.12 Definition of End of Trial ................................................................................................ 15

3 TRIAL INTERVENTIONS .................................................................................................... 15

4 SAFETY REPORTING .......................................................................................................... 15

4.1 Procedures for Reporting Adverse Events and Serious Adverse Events ............................. 16

4.1.1. Other events exempt from immediate reporting as SAEs............................................. 16

4.1.2. Procedure for immediate reporting of Serious Adverse Events ................................... 16

4.1.3 Expectedness and Causality ......................................................................................... 16

Assessment of Causality ......................................................................................................... 17

4.2 SUSAR Reporting ........................................................................................................... 17

4.3 Development Safety Update Reports .............................................................................. 17

5 STATISTICS .......................................................................................................................... 17

5.1 Master Statistical Analysis Plan (M-SAP) .......................................................................... 17

5.2 Open Adaptive Platform Trial ......................................................................................... 17

5.2.1 Co-Primary Endpoints & Analyses ............................................................................. 18

5.2.2 Adaptive Design .......................................................................................................... 19



5.2.3 Interim Analyses .......................................................................................................... 19

5.2.4 Allocation & Response Adaptive Randomisation ....................................................... 20

5.2.5 Sample Size Justification ............................................................................................. 20

5.2.6 Virtual Trial Simulations ............................................................................................. 20

5.2.7 Procedure for Accounting for Missing, Unused, and Spurious Data........................... 21

5.3 Primary Analysis Population ........................................................................................... 21

5.4 Procedures for Reporting Unplanned Deviation(s) from the Master Statistical Analysis Plan 21

5.5 Qualitative sub-study analysis ......................................................................................... 21

6 DATA MANAGEMENT ....................................................................................................... 21

6.1 Source Data ..................................................................................................................... 21

6.2 Access to Data ................................................................................................................. 22

6.3 Data Recording and Record Keeping .............................................................................. 22

7 QUALITY ASSURANCE PROCEDURES ........................................................................... 22

7.1 Risk assessment and Monitoring ..................................................................................... 22

7.2 Trial committees .............................................................................................................. 23

8 PROTOCOL DEVIATIONS .................................................................................................. 23

9 SERIOUS BREACHES .......................................................................................................... 23

10 ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 24

10.1 Declaration of Helsinki ................................................................................................... 24

10.2 Guidelines for Good Clinical Practice ............................................................................. 24

10.3 Approvals ........................................................................................................................ 24

10.4 Other Ethical Considerations ........................................................................................... 24

10.5 Reporting ......................................................................................................................... 24

10.6 Transparency in Research................................................................................................ 24

10.7 Participant Confidentiality .............................................................................................. 25

10.8 Expenses and Benefits ..................................................................................................... 25

11 FINANCE AND INSURANCE .......................................................................................... 25

11.1 Funding ............................................................................................................................ 25

11.2 Insurance ......................................................................................................................... 25

11.3 Contractual arrangements ................................................................................................ 25

12 PUBLICATION POLICY ................................................................................................... 25

13 DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL PROPERTY..................................................................................................... 26

14 ARCHIVING ...................................................................................................................... 26

21 REFERENCES .................................................................................................................... 27

22 APPENDIX A: SCHEDULE OF PROCEDURES ............................................................ 31

23 APPENDIX B: AMENDMENT HISTORY ...................................................................... 34



24 APPENDIX C: USUAL CARE ARM ................................................................................... 37

1. Background and rationale ................................................................................................... 37

2. Changes to outcome measures ............................................................................................ 37

3. Detail of intervention .......................................................................................................... 37

a. Investigational Medicinal Product (IMP) description ......................................................... 37

b. Storage of IMP .................................................................................................................... 37

4. Safety reporting ................................................................................................................... 37

25 APPENDIX D: USUAL CARE PLUS HYDROXYCHLOROQUINE ARM (DISCONTINUED) ....................................................................................................................... 38


a. Evidence for potential Hydroxychloroquine benefits in COVID-19 .................................. 38

2. Eligibility criteria specifically related to hydroxychloroquine ........................................... 42

3. Outcome measures related to hydroxychloroquine ............................................................. 43


a. Investigational Medicinal Product (IMP) description ......................................................... 43

b. Storage of IMP .................................................................................................................... 43

c. SmPC precautions and concomitant medication ................................................................. 44

i. Precautions ...................................................................................................................... 44

ii. Concomitant medication .................................................................................................. 44

iii. Pregnancy and Breastfeeding....................................................................................... 45


26 APPENDIX E: USUAL CARE PLUS AZITHROMYCIN ARM ......................................... 46


a. Evidence for potential Azithromycin benefits in COVID-19 ............................................. 46

b. Importance of treating CAP or CAP risk in the elderly or immuno-compromised ............ 46

2 Changes to outcome measures ............................................................................................ 47

3 Eligibility criteria specifically related to azithromycin ....................................................... 47

4 Detail of intervention .......................................................................................................... 47

a. Investigational Medicinal Product (IMP) description ..................................................... 48

b. Storage of IMP ................................................................................................................ 48

c. SmPC precautions and concomitant medication ............................................................. 48

i. Precautions ...................................................................................................................... 48

ii. Concomitant medications ................................................................................................ 48

iii. Fertility, pregnancy and lactation ................................................................................ 52

5 Safety reporting ...................................................................................................................... 52

26 APPENDIX F: USUAL CARE PLUS DOXYCYCLINE ARM ........................................... 53


a. Evidence for potential doxycycline benefits in COVID-19 ................................................ 53



b. Importance of treating CAP or CAP risk in the elderly or immuno-compromised ............ 53


3. Eligibility criteria specifically related to doxycycline ........................................................ 54



b. Storage of IMP ................................................................................................................ 55


i. Precautions ...................................................................................................................... 55

ii. Concomitant medications ................................................................................................ 55


26 APPENDIX G: USUAL CARE PLUS INHALED CORTICOSTEROID (ICS) ARM ........ 56


a. Evidence for potential benefits of inhaled corticosteroids in COVID-19 illness................ 56


3. Eligibility criteria specifically related to ICS...................................................................... 57



b. Storage of IMP ................................................................................................................ 57


iii. Precautions ................................................................................................................... 57

iv. Concomitant medications ............................................................................................ 57


27. Supplementary Material ...................................................................................................... 59

A. Abbreviations .................................................................................................................. 59

B. Key Trial Contacts ........................................................................................................... 60

C. Objectives and Outcome Measures ................................................................................. 62

D. Adverse Events ................................................................................................................ 64

Definitions .............................................................................................................................. 64

E. Data Recording and Record Keeping .................................................................................. 65

F. Qualitative Sub-study .......................................................................................................... 65



1. BACKGROUND and RATIONALE We urgently need to know whether potential interventions for COVID-19-like-illness that are suitable for use in the community might help affected individuals recover more quickly and reduce the risk of hospitalisation and/or death. PRINCIPLE is a platform trial designed to efficiently evaluate potential treatments for people with COVID-19-like-illness, and who may be at higher risk of poorer outcomes. Eligible participants are those who meet the UK Chief Medical Officer’s definition of COVID-19 illness, who are being managed in the community, and who are aged 50 and over with certain comorbidities, and those aged 65 and over (1-4).

The platform trial has the flexibility to allow additional interventions to be added in, or to replace existing interventions according to pre-specified criteria. If at any point a treatment is deemed superior to the usual care arm, the superior treatment may replace the usual care arm as the new standard of care. All approved intervention arms are outlined in Intervention Specific Appendices (ISAs).

The trial has co-primary endpoints: 1) Time taken to self-reported recovery; and 2) Hospitalisation and/or death. The main objective of the trial is to assess the effectiveness of the respective interventions in reducing time to recovery and in reducing the incidence of hospitalisation and/or death.

The primary analysis will be by “intention to treat”, with secondary “intention to treat infected” analyses based on identified aetiology. Clinical data, and information from swab and blood tests, where available, will be used to classify participants according to aetiology.

2. TRIAL DESIGN AND PROCEDURES PRINCIPLE is an open, prospective, individually randomised, platform, response adaptive, controlled clinical trial in community care. 2.1 Participant Identification

2.1.1 Trial Participants

The trial aims to include participants aged 50 and over with certain comorbidities, and those aged 65 and over with confirmed or possible COVID-19 who meet the case definition for COVID-19, and who are well enough to remain in the community. This definition can be found here: https://www.gov.uk/government/publications/wuhan-novel-coronavirus-initial-investigation-of-possible-cases/investigation-and-initial-clinical-management-of-possible-cases-of-wuhan-novel-coronavirus-wn-cov-infection The study is for people who have ongoing symptoms. 2.1.2 Inclusion Criteria

Participant, or their legal representative, is willing and able to give informed consent for participation in the study;

Participant is willing to comply with all trial procedures;

https://www.gov.uk/government/publications/wuhan-novel-coronavirus-initial-investigation-of-possible-cases/investigation-and-initial-clinical-management-of-possible-cases-of-wuhan-novel-coronavirus-wn-cov-infection





SARS-CoV-2 infection (suspected due to symptoms or laboratory confirmed). Onset of symptoms or a positive test for SARS-Co-V2 infection with symptoms of COVID-19 must be within the last 14 days.

Age criteria: Patients aged ≥65, or Patients aged ≥50-64 years and meeting at least one of the following criteria:

Known weakened immune system due to a serious illness or medication (e.g. chemotherapy);

Known heart disease and/or a diagnosis of high blood pressure;

Known asthma or lung disease;

Known diabetes;

Known mild hepatic impairment;

Known stroke or neurological problem;

Self-report obesity or body mass index ≥35 kg/m2

2.1.3 Exclusion Criteria

Patient currently admitted in hospital

Almost recovered (generally much improved and symptoms now mild or almost absent)

Judgement of the recruiting clinician deems ineligible.

Previous randomisation to an arm of the PRINCIPLE trial

Additional exclusions specific to each intervention arm are listed in the ISAs. For participation, participants must be eligible to be randomised to at least one intervention arm as well as the Usual Care arm. 2.2 Trial procedures

2.2.1 Recruitment

Recruitment is possible through a variety of mechanisms:

2.2.2 Face to face

Attending clinicians, including research nurses or other health care professionals, at general medical practices, paramedic services, hospital emergency departments, clinical care hubs, Hospital at Home facilities, care of the elderly services, pharmacies, social care services, residential and nursing homes, or any health and social care facility, can facilitate recruitment into the trial. They can do this by discussing the study with potentially eligible participants, guiding them through informed consent procedures, collection of baseline data, completion of screening questions, collecting information for eligibility assessment, and randomising the participant. If required and appropriate, licensed prescribers may prescribe the medication appropriate to the group to which the participant is randomised. Alternatively, health care professionals may revert to the PC-CTU to complete the activity, including eligibility confirmation and issue of study medication and materials.

2.2.3 Remote recruitment



i) All Health, health related, and Social Care professionals will be able to give information verbally or via a trial text, email, poster, social media post, adverts, media release, leaflet or letter, to potential study participants and their study partners. They may also direct patients to the online study information and the study website. ii) Potential participants may present directly to the study team via the website or by the study telephone contact. The study team can provide information about joining the trial and guide them through the consent and enrolment process. iii) A General Practice may be contacted by a potential participant or the practice may contact patients, by text (or by letter), who may match the trial eligibility criteria, through running searches of their database. They will then direct patients to the trial enrolment website or seek verbal consent to be contacted by the trial team. iv) NHS Digital will provide the PRINCIPLE trial with a daily list of contact details from the COVID-19 testing Pillar 2 data, for patients receiving a positive test result for SARS-Co-V2 infection, via a secure transfer system. NHS digital will apply an age filter to ensure only the details of those within the age range of the trial are passed on to PRINCIPLE. The trial team will make a limited number (maximum of 3) of attempts to telephone, text or email these patients to provide them with information about the trial, to invite them to consider taking part, and to enrol them if they provide full informed consent and are deemed eligible at screening. Patient details will be provided in accordance with section 251 under the General Notice under the Health Service Control of Patient Information Regulations 2002, which applies only in England and Wales, providing patient information without consent for COVID-19 public health, surveillance and research purposes. The notice provides a temporary legal basis to avoid a breach of confidentiality for COVID-19 purposes. For all recruitment models:

Study Partner: at screening the potential participant will be asked to provide contact details for a Study Partner, to assist in completing trial procedures and to provide information on their behalf where necessary, but this is not a requirement for trial participation. However, it is strongly encouraged that participants who may be frailer and/or lack capacity to consent make use of a study partner to facilitate their participation. In addition to family member or friend, the study partner may also be a carer or other suitable person.

Participants may be asked if they wish to enrol in additional studies that do not conflict with the main PRINCIPLE trial. Those who do not screen as eligible for PRINCIPLE may be alerted to the possibility of participating in other approved trials.

2.3 Screening

An online screening, eligibility and consent procedure is used. If online access is not possible, a member of the trial team collects this information during a telephone call. A trial free-phone number enables participants to contact the trial team for further information and study participation support. Participants are screened after they have read the PIS by completing an online eligibility questionnaire.



2.4 Informed Consent

If participants meet the screening criteria, they will be asked to provide informed consent and a screening trial ID number will be assigned to them. Remote, paperless online/telephone consent is required, and appropriate during the pandemic. Participants will be able to download their consent form, or it may be printed by the central study team and delivered to participants with their study materials if they so prefer. Written and verbal versions of the PIS and ICF will be presented to participants detailing no less than: the exact nature of the trial; the known side-effects and risks involved in taking part. It will be clear that the participant is free to withdraw from the study at any time. A summary, pictorial PIS is available which can be read by those feeling very unwell, lack capacity or have low reading comprehension skills. Adequate time will be given to the participant to consider the information and to ask any questions about the trial before deciding whether to participate. After consent, the participant will enter online baseline information, including their address, contact details and those of a Study Partner. Population groups such as care home residents have been amongst those hardest hit by the pandemic and therefore stand to benefit the most from any effective treatments. However, some care home residents lack capacity to consent to research themselves. If the recruiting clinician deems a care home resident lacks capacity to consent then a personal or professional legal representative (England and Wales only) will be asked to provide consent for those lacking capacity to consent for themselves. A personal legal representative is defined as a person not connected with the conduct of the trial who is suitable to act as the legal representative by virtue of their relationship with the adult. A professional legal representative may be a doctor responsible for the medical treatment of the adult if they are independent of the study, or a person nominated by the healthcare provider. In all instances, a personal legal representative will be sought first and a professional legal representative sought only if a personal legal representative cannot be identified. A professional legal representative will be sought in order not to deny access to research to older adults who may not have personal legal representatives. Only residents of care homes who lack capacity to consent will be recruited, adults who lack capacity to consent will not be recruited from the wider community. Residents who, in addition to their lack of capacity, have a quality of life which can reasonably be seen as not acceptable to them will not be recruited The legal representative will be provided with information about the trial and made aware of the following:

They are being asked to give consent on behalf of the incapacitated adult,

They are free to decide whether they wish to make this decision or not, and

They are being asked to consider what the adult would want, and to set aside their own personal views when making this decision.



2.5 Eligibility Assessment Eligibility of those who have provided appropriate consent can be checked at study sites or centrally by a medically qualified clinician or a research nurse, who is suitably trained and experienced and has been delegated this responsibility, and who has appropriate access to the participant’s summary care record or relevant medical information. If a participant’s summary care record cannot be accessed centrally, the clinician/delegate will contact the participant’s primary care medical practice for information relevant to confirming eligibility. Participants will not be randomised to an arm if an exclusion criterion to that arm applies to them, but will need to have no exclusions relevant to at least one intervention and the usual care arm. 2.6 Randomisation

Participants will be randomised using a fully validated and compliant web-based randomisation system called Sortition. Once deemed eligible, the clinician or a member of the trial team will randomise the participant, to one of the arms they are eligible for (at least two arms), automatically by Sortition. Full details of response adaptive randomisation are described in section 5.2. The participant, legal representative if applicable, trial team and participant’s GP will be notified electronically of the treatment allocation. If the participant does not have an email address, they will be notified by telephone. The research team may also send the GP or Care Home an email or letter via secure systems, containing personally identifiable data and treatment allocation. 2.7 Blinding and code-breaking

PRINCIPLE is an open-label trial. The participant, legal representative if applicable and the recruiting clinician will know the participant’s allocation. Therefore, no unblinding or code breaking is required. However, those managing the data will be blind to participant allocation. The trial team and recruiting clinicians will be blinded to emerging results. During the course of the trial, only those on the Data Safety and Monitoring Committee will have access to the unblinded interim results. 2.8 Baseline Assessments

Once randomised, study medication (if so randomised), and a participant pack will be sent to participants, from their general practice, study team, Public Health England (PHE) or other approved central service (or collected from a general practice or pharmacy). Participants may be offered a swab test as part of standard care. Where possible, and availability of sampling kits allows, one sample will be taken as close to study entry as possible to assess COVID-19 status and other viral aetiologies. While the aim is to have a swab result for all patients, where swabs are unavailable, patients may still participate and be included in the primary intention to treat analysis only.



2.9 Subsequent Visits There is no requirement for participants to have a face-to-face visit as part of trial participation. All subsequent measurements consist of self-completed questionnaires online or through telephone calls, and primary care and/or hospital record searches. We will ascertain relevant data from primary care and/or hospital medical records about length of hospital stay, oxygen therapy, and ICU admission and ventilation, if applicable. Participants will be sent a link to their online diary, which they will be asked to complete for 28 days. They will be asked to rate the severity of symptoms, record contacts with the health services (including hospital admission), record medication use and new infections in the household. It is becoming increasingly apparent the COVID-19 infection may have a considerable negative impact on well-being (14) and so the five questions of WHO-5, validated for measuring wellbeing over time, will be presented at baseline and on days 14 and 28. We will not ask for WHO-5 questions to be completed for participants who lack capacity. We will capture ethnicity and care home residency at baseline and day 28 (if missed at baseline). All participants receive a call from the trial team on day 2/3 to confirm that they have received a participant pack, and trial medication (if randomised to a trial medication), and to explain that they should complete the daily diary for 28 days even if they feel better or their swab result is negative. The trial team calls participants/study partners on days 7, 14 and 28 if they do not have internet access or have not completed their diary for at least 2 consecutive days prior to the call. No more than six contact attempts will be made at each of these follow-up points. We will seek consent from participants to contact them on a monthly basis for up to 12 months after enrolment (via email, text message or phone call) to collect information about any ongoing symptoms, hospitalisations and well-being. We will re-consent those already enrolled in the trial. In addition to the swab being undertaken as part of the national RCGP RSC surveillance programme with PHE, trial participants will also be asked to consent to the trial team accessing a blood sample result. The study team will obtain the result from RCGP RSC/PHE. The RCGP RSC will report to the central trial office at regular intervals about healthcare contacts in the participant’s clinical records, as they are able to download this information centrally. This will be used as confirmation and a back-up for information obtained directly from study participants and other data sources outlined above. If obtaining data is not possible using this route, the GP surgery will be contacted to request a limited notes review. Participant records will be accessed up to twelve months following enrolment to ascertain follow up data from enrolment to day 28. Data will be collected as close to real time as possible; RCGP RSC, EMIS and NHS Digital and other sources of routinely collected data will be utilised if required To investigate the impact of trial interventions on the longer-term effects of COVID-19, we will use these data collection methods to follow-up participants, for up to 10 years. 2.10 Qualitative Sub-study



A qualitative sub-study will be nested within the trial, to capture data to understand how patients conceptualise their illness and how they respond to taking medication(s) as part of the trial. Once participants have completed the trial, we will interview their respective clinicians to explore their views of taking part in trials during a pandemic. Healthcare professionals will also be asked about their experiences of taking part in the trial. See supplementary material E for further details. Participants who lack capacity will not be invited to participate in the qualitative sub study. 2.11 Early Discontinuation/Withdrawal of Participants

Each participant, or their legal representative on the participant’s behalf, has the right to withdraw from the study at any time. For those that lack capacity, expression of dissent in any form will be taken as an indication they do not wish to be included and they will be withdrawn. In addition, the Investigator may discontinue a participant from the study at any time if the Investigator considers it necessary for any reason including: • Ineligibility (either arising during the study or retrospectively having been overlooked at

screening) • Withdrawal of consent The reason for withdrawal will be recorded on the CRF. Data that has already been collected about the participant will be kept and used. 2.12 Definition of End of Trial

Last data capture of last participant, when: no further suitable interventions are available and/or COVID-19 is no longer prevalent. March 2022 has been decided as the formal end date at this stage, but this date may need to be amended depending on circumstances prevailing at the time. 3 TRIAL INTERVENTIONS

IMP information can be found in the relevant ISAs. In general, re-packaging and issuing of medication can be completed by: the patient’s registered GP surgery or treatment and assessment facility; an accredited licensed central facility; an online, community or hospital pharmacy, and The Primary Care Clinical Trials Unit (as approved by the MHRA). Distribution of trial packs to participants will be tracked via courier or call/text message. Clinicians can prescribe trial medications that can be issued in the community and pharmacies can issue medication to the patient by community pharmacy services ‘on-line pharmacy’ services, NHS volunteers, or it can be collected from the pharmacy by the participant or someone on their behalf. To record presence of symptoms and severity, as well as adherence to trial treatment, participants will receive a daily email asking them to complete an online diary where they will record their symptoms and medicines use. If incomplete, the trial team will contact the participant and/or their Study Partner to obtain the data. A risk-adapted approach will be used for drug accountability. Accountability logs will be kept by PC-CTU when they ship drug. 4 SAFETY REPORTING



All symptoms, medication side-effects and SAEs will be collected from participant daily diaries, calls to participants/Study Partners, medical records, notes reviews and RCGP data downloads. SAE information will be analysed as part of the interim and whole trial analysis and will be reviewed at each Data Safety & Monitoring Committee meeting.

4.1 Procedures for Reporting Adverse Events and Serious Adverse Events The severity of events will be assessed by participants in daily diaries on the following scale: minor problem/moderate problem/major problem. Serious Adverse Events (SAE), but not Adverse events (AE), will be assessed for causality and expectedness in the trial. A participant may voluntarily withdraw from treatment due to what he or she perceives as an intolerable AE. Hospitalisation and/or death due to confirmed or possible SARS-Cov-2 infection is a primary outcome, we will collect this data using a risk-adapted approach and will not report such SAEs. SAEs other than hospitalisation or death due to COVID-19 must be reported by the person who has discovered the SAE or nominated delegate within 24 hours of becoming aware of the event. The sponsor or delegate will ensure it is reviewed by the CI or other delegated personnel for relatedness and expectedness as soon as possible taking into account the reporting time for a potential SUSAR according to the relevant competent authority. If the event has not resolved, at the 28 day time point the SAE will be reviewed again to see if resolution has occurred. If the event is considered ‘resolved’ or ‘resolving’ no further follow up is required. If not, the event must be followed up until such a time point. See Appendix C for definitions of adverse events 4.1.1. Other events exempt from immediate reporting as SAEs

Hospitalisations will be defined as at least a one night admission to hospital. Hospitalisation for a pre-existing condition, including elective procedures planned prior to study entry, which has not worsened, does not constitute an SAE, and standard supportive care for the disease under study are not SAEs and do not require SAE reporting. 4.1.2. Procedure for immediate reporting of Serious Adverse Events

Trial team will complete an SAE report form for all reportable SAEs.

GP practice/trial team/RCGP will provide additional, missing or follow up information in a timely fashion.

The CI or delegate will review the SAE once reported, collect as much information and report to the Sponsor within the timeframe according to the PC-CTU SOPs. 4.1.3 Expectedness and Causality

For SAEs that require reporting, expectedness of SARs will be determined according to the relevant RSI section of the Summary of Product Characteristics/IB. The RSI will be the current Sponsor and MHRA approved version at the time of the event occurrence.



Assessment of Causality

The relationship of each serious adverse event to the trial medication must be determined by a medically qualified individual according to the following definitions:

Unrelated – where an event is not considered to be related to the IMP

Possibly – although a relationship to the IMP cannot be completely ruled out, the nature of the event, the underlying disease, concomitant medication or temporal relationship make other explanations possible.

Probably – the temporal relationship and absence of a more likely explanation suggest the event could be related to the IMP.

Definitely – the known effects of the IMP, its therapeutic class or based on challenge testing suggest that the IMP is the most likely cause.

All SAEs labelled possibly, probably or definitely will be considered as related to the IMP.

4.2 SUSAR Reporting

All SUSARs will be reported by the sponsor delegate to the relevant Competent Authority and to the REC and other parties as applicable. For fatal and life-threatening SUSARS, this will be done no later than seven calendar days after the Sponsor or delegate is first aware of the reaction. Any additional relevant information will be reported within eight calendar days of the initial report. All other SUSARs will be reported within 15 calendar days. Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the same Sponsor, whether or not the event occurred in the current trial. 4.3 Development Safety Update Reports

The DSUR will be developed and submitted annually on the anniversary date that the trial receives Clinical Trial Authorisation +60 days. Due to the nature of this trial and the importance of sharing the science of COVID-19 and the drug, internationally, we expect to produce reports to the UK Government and regulatory agency more frequently upon request. 5 STATISTICS

5.1 Master Statistical Analysis Plan (M-SAP) Details of the statistical design and methods will be described in a Master Statistical Analysis Plan (M-SAP), in which an appendix to the M-SAP titled “Adaptive Design Report” (ADR) provides complete specifications for the primary analysis and pre-specified adaptive algorithm. In addition, the M-SAP will be accompanied by arm-specific appendices to describe any planned deviations from the M-SAP. A broad overview of the design and primary analyses is provided below. 5.2 Open Adaptive Platform Trial

PRINCIPLE is an open, adaptive, platform trial to evaluate emerging treatments for symptomatic COVID-19-like illness. A “platform trial” is a trial in which multiple treatments for the same



disease are tested simultaneously. The backbone of the trial is an adaptive clinical trial design. Pre-specified decision criteria allow for dropping a treatment for futility, declaring a treatment superior, or adding a new treatment to be tested. If at any point a treatment is deemed superior to the Usual Care arm, the superior treatment may replace the Usual Care arm as the new standard of care. Because the process of dropping and adding treatments may be on-going for an indefinite period of time, platform trials may be better conceived of as a process rather than a singular clinical trial. In the context of the COVID-19 pandemic, the trial may continue as long as the pandemic persists. The PRINCIPLE trial will begin as a two arm, 1:1 randomised trial but will have the capability to add additional interventions over time. The evaluation of any new interventions will be governed by this master protocol and M-SAP (including adaptive algorithm and decision criteria), with any planned deviations from the master protocol and M-SAP to be specified in arm-specific appendices. The inclusion of any new interventions will require additional arm-specific appendices to the master protocol and M-SAP. 5.2.1 Co-Primary Endpoints & Analyses

There are two co-primary endpoints. The first co-primary endpoint is time to recovery from possible COVID-19 infection within 28 days from randomization, where time to recovery is defined as the first instance that a participant reports feeling recovered. The second co-primary endpoint is hospital admission or death related to possible or confirmed COVID-19 within 28 days from randomization. Unless otherwise specified in the ISAs, the co-primary outcomes will be evaluated using a “gate-keeping” strategy. For a given treatment, the hypothesis for the time to recovery endpoint will be evaluated first, and if the recovery null hypothesis is rejected, the hypothesis for the second co-primary endpoint of hospitalization/death will be evaluated. This gate-keeping strategy preserves the overall Type I error of the primary endpoints without additional adjustments for multiple hypotheses. In addition, the gate-keeping structure reflects the clinical belief that an intervention is unlikely to demonstrate benefit on the hospitalization/death endpoint without first demonstrating benefit on the time to recovery endpoint. The primary outcome of time to recovery is defined as the first instance that a participant reports feeling recovered. The corresponding primary analysis for this outcome is a Bayesian piecewise exponential model, with time to recovery regressed on treatment and stratification covariates

(age, comorbidity). Let j denote the log hazards ratio comparing the hazards of recovery for participants in treatment group j versus participants in the Usual Care arm. A corresponding Bayesian posterior distribution will be derived for the estimated log hazards ratio. The first co-primary analysis for intervention j will test the following hypothesis: H10: j ≤ 0 H11: j > 0 If the Bayesian posterior probability of superiority (a log hazards ratio greater than 0 corresponding to quicker recovery) for a treatment versus Usual Care is sufficiently large (e.g. ≥0.99), the null hypothesis will be rejected and the intervention will be deemed superior to Usual Care with respect to time to recovery. The exact threshold of the superiority decision criterion (e.g. 0.99) will be determined a priori via simulation to control the one-sided Type I error of the



study at approximately 0.025, and will be specified in the Adaptive Design Report (Appendix to the M-SAP). The Adaptive Design Report will also specify appropriate methodology for the primary analysis when the Usual Care arm is replaced by a superior treatment, and for when the comparison of a treatment versus Usual Care includes non-concurrent randomisations. The second co-primary endpoint is hospital admission or death due to possible SARS-CoV-2 infection. The corresponding analysis will be a Bayesian generalised linear model of hospitalisation/death regressed on treatment and stratification covariates (age, comorbidity).

Let j denote the log odds ratio comparing the odds of hospitalisation/death for persons in treatment group j versus persons in the Usual Care arm. A corresponding Bayesian posterior distribution will be derived for the estimated log odds ratio. If the first co-primary endpoint hypothesis (for time to recovery) is rejected for intervention j, the second co-primary hypothesis for intervention j be tested: H20: j ≤ 0 H21: j > 0 If the Bayesian posterior probability of superiority on hospitalization/death for a treatment versus Usual Care is sufficiently large (e.g. ≥ 0.99), the null hypothesis will be rejected and the intervention will be deemed superior to Usual Care with respect to hospitalization/death. The exact threshold of the superiority decision criterion (e.g. 0.99) will be determined a priori via simulation to control the one-sided Type I error of the study at approximately 0.025, and will be specified in the M-SAP. 5.2.2 Adaptive Design

The pre-specified design will allow adaptations to the trial based on the observed co-primary endpoint data. These adaptations include the declaration of success or futility of an intervention at an interim analysis, the addition or removal of treatment arms, and changes in the randomisation probabilities. Adaptations will occur at a given interim analysis if pre-specified conditions are satisfied. The adaptive algorithm will be documented in the Adaptive Design Report, including pre-specified criteria for decisions regarding futility or effectiveness of interventions and/or replacing interventions in the trial. 5.2.3 Interim Analyses

Precise timing of the first interim analysis and frequency of subsequent interim analyses will be specified in the Adaptive Design Report, based on both simulations and logistical considerations. At each interim analysis, all enrolled intervention arms will be evaluated for success and futility on both co-primary endpoints using the Bayesian primary analyses. These interim analyses will maintain the gate-keeping sequential order by first evaluating the hypothesis for time to recovery, and if the recovery endpoint null hypothesis is rejected, subsequently evaluating the hypothesis for hospitalisation and/or death. If the Bayesian posterior probability of superiority of a given intervention versus Usual Care is sufficiently large for a given endpoint (e.g. ≥ 0.99) within the gate-keeping structure, superiority will be declared versus Usual Care with respect to that endpoint.



If the Bayesian posterior probability of a clinically meaningful treatment effect is sufficiently small (e.g. < 0.01) for the first co-primary endpoint (time to recovery), the intervention arm may be dropped from the study for futility. If there are no other intervention arms available, the trial may be suspended; otherwise accrual continues to the remaining treatment arms. The exact futility thresholds will be pre-specified in the Adaptive Design Report and determined via simulation. 5.2.4 Allocation & Response Adaptive Randomisation

Initially, randomisation will be fixed 1:1 for a comparison between two trial arms, with stratification by age (less than 65, greater than or equal to 65), and comorbidity (yes/no). If a second experimental intervention arm is added to the study, randomisation allocation will be modified and the additional intervention will be included in the interim analyses (with evaluation for success and futility) as detailed in the Adaptive Design Report. If there are at least 3 arms (2 intervention arms plus Usual Care) in the study, each interim analysis may incorporate modified randomisation probabilities via response adaptive randomisation (RAR). Full details for implementing RAR will be provided in the Adaptive Design Report; the general idea is to allocate more participants to the intervention arms that have the best observed outcomes. 5.2.5 Sample Size Justification

Given the open perpetual trial structure, the trial does not have a finite ending based on sample size. Rather, the trial will continue until either superiority or futility is claimed for each intervention, or until the pandemic expires in the population. We estimate that approximately 400 participants per arm (800 participants total if only a single intervention vs. Usual Care) will be required to provide 90% power for detecting a hazard ratio of 1.3 (approximate difference of 2 days in median recovery time). This calculation is based on the assumption of an exponential distribution for time to recovery with a median of 9 days in the Usual Care arm, with some adjustments for missing data and multiple interim analyses. On average, we expect fewer participants to be required when there is a large treatment benefit or complete lack of benefit. For example, if the true hazard ratio is 1.5 (3 day benefit in median time to recovery), on average only 150 subjects per arm are required to provide sufficient power. The primary advantage of the adaptive design is the ability to adapt the sample size to the observed data, thus addressing the primary hypothesis as quickly and as efficiently as possible. We estimate that approximately 1500 participants per arm (3000 participants total if only a single intervention vs. usual care) will be required to provide 90% power for detecting a 50% reduction in the relative risk of hospitalisation and/or death. This calculation is based on the assumption of an underlying 5% combined hospitalisation and/or death rate in the Usual Care arm, with an intervention lowering the hospitalisation and/or death rate to 2.5%, with some adjustments for the multiple interim analyses. We expect fewer participants to be required to detect a 50% reduction if the event rate in the Usual Care arm is greater than 5%. 5.2.6 Virtual Trial Simulations

Because of the adaptive platform trial structure, there exists no simple formula(s) to calculate power and Type I error (false positive rate). Hence, virtual trial simulations will be used to fully characterize and quantify the power and Type I error of the design. These simulations will be



conducted prior to the first interim analysis (with results described in the Adaptive Design Report), and will be used to optimize the adaptive decision criterion and RAR parameters. The simulations will include a comprehensive evaluation of trial performance across a wide range of assumptions (e.g. underlying distribution of outcome in Usual Care arm, treatment effect, accrual rates, etc.). This will include summaries regarding the number of subjects required to make a success or futility conclusions for each intervention. Complete details of the simulations will be provided in the Adaptive Design Report. 5.2.7 Procedure for Accounting for Missing, Unused, and Spurious Data.

Full details of handling missing data will be specified in the M-SAP. 5.3 Primary Analysis Population

The primary analysis population is defined as all randomised participants according to the groups they were randomly allocated to, regardless of deviation from protocol and irrespective of their COVID-19 status. Secondary analyses will conduct the primary analysis on the subset of participants with confirmed COVID-19. 5.4 Procedures for Reporting Unplanned Deviation(s) from the Master Statistical Analysis Plan

Analyses will be carried out in accordance with the M-SAP and corresponding appendices. Any additional analysis that is not specified in the M-SAP/appendices or any unplanned deviation(s) from the M-SAP/appendices will be specified in the Statistical Report. Reasons for these changes will be documented and authorised by the Chief Investigator.

5.5 Qualitative sub-study analysis

Audio-recordings of interviews will be transcribed verbatim and transcripts analysed using thematic analysis. Patient and HCP interviews transcripts will be analysed separately but findings will be compared and triangulated if deemed appropriate. Thematic analysis allows the research team to take a pragmatic approach to data collection, remaining grounded in the data but ensuring that the analysis answers the research objectives. NVivo software will be used to assist with the organisation and coding of data. Codes will be compared with one another to create categories, grouping similar codes together. A thematic framework will be developed to code all data and represent key themes for both sets of interviews. 6 DATA MANAGEMENT

The data management aspects of the study are summarised here with details fully described in the Data Management Plan. 6.1 Source Data

Source documents are where data are first recorded. These include, but are not limited to, hospital records (from which medical history and previous and concurrent medication may be summarised into the CRF), clinical and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence.



If a participant fails to complete data online and after six attempts at contacting the participant/Study Partner, the RCGP RSC may be utilised to obtain missing data. Data collected will include participant identifiable information and will be accessed at the University of Oxford according to PC-CTU Information Governance policies and GDPR. Data will only be held for the duration it is required, this will be reviewed annually. CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no other written or electronic record of data). All documents will be stored safely in confidential conditions. On all study-specific documents, other than the signed consent, the participant will be referred to by the study participant number/code, not by name. 6.2 Access to Data

Direct access will be granted to authorised representatives from the Sponsor and host institution for monitoring and/or audit of the study to ensure compliance with regulations. 6.3 Data Recording and Record Keeping

A CTU data manager will oversee the receiving, entering, cleaning, querying, analysing and storing all data that accrues from the study by designated persons. The Investigators will maintain appropriate medical and research records for this trial, in compliance with the requirements of the Medicines for Human Use (Clinical Trial) Regulations 2004, ICH E6 GCP and regulatory and institutional requirements for the protection of confidentiality of volunteers. The Chief Investigator, Principal Investigator, Co-Investigators, clinical team, including Clinical Research Nurses, and other authorised members of the trial team will have access to records. The Investigators will permit authorised representatives of the sponsor, and regulatory agencies to examine (and when required by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits and evaluation of the study safety and progress. The software used for the trial is described in supplementary material D. 7 QUALITY ASSURANCE PROCEDURES

The study will be conducted in accordance with the current approved protocol, GCP, relevant regulations and PC-CTU Standard Operating Procedures. All PIs, coordinating centre staff and site staff will receive training in trial procedures according to GCP where required. Regular monitoring will be performed according to GCP using a risk-based approach. Data will be evaluated for compliance with the protocol and accuracy in relation to source documents where possible. The PC-CTU Trial Management Group will be responsible for the monitoring of all aspects of the trial’s conduct and progress and will ensure that the protocol is adhered to and that appropriate action is taken to safeguard participants and the quality of the trial itself. The TMG will be comprised of individuals responsible for the trial’s day to day management and will meet regularly throughout the course of the trial. 7.1 Risk assessment and Monitoring



A risk assessment and monitoring plan will be prepared before the study opens and will be reviewed as necessary over the course of the study to reflect significant changes to the protocol or outcomes of monitoring activities. Monitoring will be performed by the PC-CTU Quality Assurance Manager or delegate. The level of monitoring required will be informed by the risk assessment. 7.2 Trial committees

The responsibilities of each group are as follows: • Data Monitoring and Safety Committee (DMSC) - to review the data at each interim

analysis as described in the Statistical Analysis section, as the updates to the randomisation scheme occur in order to ensure that the process is working correctly and to review and monitor the accruing data to ensure the rights, safety and wellbeing of the trial participants.

Trial Steering Committee (TSC) - the Trial Steering Committee ensure the rights, safety and wellbeing of the trial participants. They will make recommendations about how the study is operating, any ethical or safety issues and any data being produced from other relevant studies that might impact the trial.

Trial Management Group (TMG) - is responsible for the day-to-day running of the trial, including monitoring all aspects of the trial and ensuring that the protocol is being adhered to. It will include Co-Investigators and will meet weekly in the first instance.

A core project team (PT) from within the TMG will meet daily as required for daily operational decision making.

8 PROTOCOL DEVIATIONS

A study related deviation is a departure from the ethically approved study protocol or other study document or process (e.g. consent process or administration of study intervention) or from Good Clinical Practice (GCP) or any applicable regulatory requirements. Any deviations from the protocol will be documented in a protocol deviation form and filed in the study master file. A PC-CTU SOP is in place describing the procedure for identifying non-compliances, escalation to the central team and assessment of whether a non-compliance /deviation may be a potential Serious Breach. 9 SERIOUS BREACHES

A “serious breach” is a breach of the protocol or of the conditions or principles of Good Clinical Practice which is likely to affect to a significant degree –

(a) the safety or physical or mental integrity of the trial subjects; or (b) the scientific value of the research.

In the event that a serious breach is suspected the Sponsor must be contacted within one working day. In collaboration with the CI, the serious breach will be reviewed by the Sponsor and, if appropriate, the Sponsor will report it to the approving REC committee and the relevant NHS host organisation within seven calendar days.



10 ETHICAL AND REGULATORY CONSIDERATIONS

10.1 Declaration of Helsinki

The Investigator will ensure that this study is conducted in accordance with the principles of the Declaration of Helsinki. 10.2 Guidelines for Good Clinical Practice

The Investigator will ensure that this trial is conducted in accordance with relevant regulations and with Good Clinical Practice. 10.3 Approvals

Following Sponsor approval, the protocol, informed consent form, participant information sheets and any proposed informing material will be submitted to an appropriate Research Ethics Committee (REC), regulatory authorities, and host institution(s) for written approval. The PI and coordinating centres for each country will ensure and confirm correct regulatory approvals are gained prior to recruitment. The Investigator will submit and, where necessary, obtain approval from the above parties for all substantial amendments to the original approved documents. 10.4 Other Ethical Considerations

If a particular arm is deemed futile and dropped, no further participants will be randomised to this arm and anyone who is currently on this arm will be informed it has been dropped. Once a particular intervention has been declared superior and effective, that will become the comparator arm (i.e. standard care). The vast majority of participant’s, due to their co-morbidities, will be exempt from prescription charges. All participants will receive a £20 voucher to cover any prescriptions and other expenses they may incur as a consequence of study participation. Participants who lack capacity to consent for themselves will only be recruited after consultation with their legal representative. Any sign of dissent in any form from the participant who lacks consent will be taken as an indication they do not wish to be involved and they will be withdrawn. Only residents of care homes who lack capacity to consent will be recruited, adults who lack capacity to consent will not be recruited from the wider community. 10.5 Reporting

The CI shall submit once a year throughout the clinical trial, or on request, an Annual Progress Report to the REC, HRA (where required), host organisation, funder (where required) and Sponsor. In addition, an End of Trial notification and final report will be submitted to the MHRA, the REC, host organisation and Sponsor. 10.6 Transparency in Research

Prior to the recruitment of the first participant, the trial will have been registered on a publicly accessible database. Results will be uploaded to the European Clinical Trial (EudraCT) Database



within 12 months of the end of trial declaration by the CI or their delegate. Where the trial has been registered on multiple public platforms, the trial information will be kept up to date during the trial, and the CI or their delegate will upload results to all those public registries within 12 months of the end of the trial declaration. 10.7 Participant Confidentiality

The study will comply with the General Data Protection Regulation (GDPR) and Data Protection Act 2018, which require data to be de-identified as soon as it is practical to do so. The processing of the personal data of participants will be minimised by making use of a unique participant study number only on all study documents and any electronic database(s). All documents will be stored securely and only accessible by study staff and authorised personnel. The study staff will safeguard the privacy of participants’ personal data. 10.8 Expenses and Benefits

All participants will be reimbursed with a £20 voucher, to cover the payment of a prescription, should they incur this as a result of study participation, and a token of recognition of giving their time and contribution to the study. The vast majority of participants will not have to pay a prescription change, should a prescription be issued as a result of trial participation. Most people with the co-morbidities outlines and in the age-range required for eligibility, are not required to pay for prescriptions. Participants who complete a telephone interview as part of the qualitative sub-study will be reimbursed with a (second) £20 voucher for their time to participate. 11 FINANCE AND INSURANCE

11.1 Funding

The study is funded by the UKRI/NIHR via an MRC call. 11.2 Insurance

The University has a specialist insurance policy in place, which would operate in the event of any participant suffering harm as a result of their involvement in the research (Newline Underwriting Management Ltd, at Lloyd’s of London). NHS indemnity operates in respect of the clinical treatment that is provided. 11.3 Contractual arrangements

Appropriate contractual arrangements will be put in place with all third parties. 12 PUBLICATION POLICY

The Investigators (those listed on the protocol and others to be decided at publication) will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any other publications arising from the study. Authors will acknowledge the study funders. Authorship will be determined in accordance with the ICMJE guidelines and other contributors will be acknowledged.



13 DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL PROPERTY

Ownership of IP generated by employees of the University vests in the University. The University will ensure appropriate arrangements are in place as regards any new IP arising from the trial. 14 ARCHIVING

Archiving will be done according to the UOXF PC-CTU SOP and study specific working instructions.



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https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf

https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf



21. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020. 22. Mahevas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844. 23. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. 24. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020. 25. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020. 26. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020. 27. Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020;49(2):215-9. 28. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949. 29. Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci U S A. 2016;113(50):14408-13. 30. E Bosseboeuf MA, T Nhan, JJ de Pina, JM Rolain, D Raoult, et al. Azithromycin inhibits the replication

of Zika virus. J Antivirals Antiretrovirals. 2018;10:6-11. 31. Madrid PB, Panchal RG, Warren TK, Shurtleff AC, Endsley AN, Green CE, et al. Evaluation of Ebola Virus Inhibitors for Drug Repurposing. ACS Infect Dis. 2015;1(7):317-26. 32. Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, et al. Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial. JAMA. 2015;314(19):2034-44. 33. Villarino AV, Kanno Y, O'Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol. 2017;18(4):374-84. 34. Hodge S, Hodge G, Holmes M, Jersmann H, Reynolds PN. Increased CD8 T-cell granzyme B in COPD is suppressed by treatment with low-dose azithromycin. Respirology. 2015;20(1):95-100. 35. Hodge S, Hodge G, Jersmann H, Matthews G, Ahern J, Holmes M, et al. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178(2):139-48. 36. Hodge S, Reynolds PN. Low-dose azithromycin improves phagocytosis of bacteria by both alveolar and monocyte-derived macrophages in chronic obstructive pulmonary disease subjects. Respirology. 2012;17(5):802-7. 37. Baines KJ, Wright TK, Gibson PG, Powell H, Hansbro PM, Simpson JL. Azithromycin treatment modifies airway and blood gene expression networks in neutrophilic COPD. ERJ Open Res. 2018;4(4). 38. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-72. 39. Kawai S, Ochi M, Nakagawa T, Goto H. Antimicrobial therapy in community-acquired pneumonia among emergency patients in a university hospital in Japan. J Infect Chemother. 2004;10(6):352-8. 40. Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med. 1999;159(21):2562-72. 41. Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020.



42. Kim HS, Luo L, Pflugfelder SC, Li DQ. Doxycycline inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2005;46(3):840-8. 43. Clemens DL, Duryee MJ, Sarmiento C, Chiou A, McGowan JD, Hunter CD, et al. Novel Antioxidant Properties of Doxycycline. Int J Mol Sci. 2018;19(12). 44. Hsu AT, Barrett CD, DeBusk GM, Ellson CD, Gautam S, Talmor DS, et al. Kinetics and Role of Plasma Matrix Metalloproteinase-9 Expression in Acute Lung Injury and the Acute Respiratory Distress Syndrome. Shock. 2015;44(2):128-36. 45. NICE. COVID-19 rapid guideline: managing suspected or confirmed pneumonia in adults in the community. NICE; 2020.

46. The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 Preliminary Report. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2021436 47. The WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group. Association Between. Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA 2020 doi: 10.1001/jama.2020.17023



22 APPENDIX A: SCHEDULE OF PROCEDURES

Procedures Participant contacts

Visit timing

Day 0

Day 0

Day 0

Day 0

Daily Day 1-28 incl

Day 28-12 months

(monthly contact)

Day 29-12mths

Up to 10 years

Screening completed

by participant

online/phone

Eligibility completed

by participant

online/phone

Baseline completed

by participant

online/phone

Eligibility completed

by Clinician online/phone

Symptom Diaries

completed by

participant online/phone

Contacted by study team if consent

provided

Retrospective data

collection by study team

By data extraction

from clinical records

Informed consent

X X X X X

Demographics X X X X

Medical history

X X X X X

Swab as part of the RCGP RSC/PHE national surveillance programme

When available,

preferably by self-

swabbing at study entry

Concomitant medications

X X

Eligibility assessment

X X



Randomisation X

Dispensing of trial drugs

X X

Questionnaire X X

WHO 5 Well Being Index

X Day 14 and day 28

X

Telephone interview (for subset of patient participants)

X

Compliance X

Adverse event assessments

X* X

Optional SARS- CoV-2 blood test as part of the RCGP RSC/PHE national surveillance programme

X

Evidence of sequalae and health care utilisation

X X



* Patient reported AEs will not be assessed by a clinician. The only exception is AEs collected from the hydroxychloroquine group. Participants in this group, will receive a telephone call on day 7 from the trial team to collect any information about cardiovascular Adverse Events (please see hydroxychloroquine appendix). Such events will be assessed by a clinician.



23 APPENDIX B: AMENDMENT HISTORY

Amendment No.

Protocol Version No.

Date issued

Author(s) of changes

Details of Changes made

1 (SA1) 1.1 Emma Ogburn; Chris Butler; Gail Hayward

Inclusion criteria: change ‘known heart disease’ to ‘Known heart disease and/or hypertension’; Exclusion criteria: exclude patients taking the following drugs: penicillamine, amiodarone, ciclosporin, chloroquine. Update section 9.6 to include vision changes and lowering of blood sugar. Update change in Funder and update Investigator list to reflect UKRI funder bid.

2 (SA2) 2.0 Emma Ogburn; Chris Butler; Gail Hayward, Hannah Swayze

Inclusion of TSC; central facility to distribute patient packs; addition of third arm; update of secondary outcomes to include WHO wellbeing questions; qualitative sub study; sign posting to other RCGP RSC study; eligibility confirmation by research nurse.

3 (SA3) 2.1 Hannah Swayze; Chris Butler; Emma Ogburn; Gail Hayward

Trial rationale; secondary outcomes to include blood test; 14 days of covid-19 symptoms; call to participant at day 2; poster

4 (SA4) 2.1 No changes to the protocol

5 (SA5) 3.0 Hannah Swayze; Chris Butler; Emma Ogburn; Gail Hayward

Updated Azithromycin information; broadening of inclusion criteria; first interim analysis; primary analysis details; care home materials; administrative and typographical updates; study partner letter; recruitment via social media, care homes and pharmacies; GPs prescribe trial medication; eligibility to at least one intervention arm as well as the



Usual Care arm; ICF may be sent to participants.

6 (SA6) 4.0 Chris Butler; Emma Ogburn; Gail Hayward; Ben Saville; Ly-Mee Yu; Hannah Swayze

Updating inclusion criteria; updating the rationale and evidence for safety of hydroxychloroquine; inclusion of a new arm, doxycycline; AE reporting for hydroxychloroquine arm; typographical clarifications.

7 (NS1) 4.0 No changes to the protocol

8 (SA7) 5.0 Chris Butler; Emma Ogburn; Ben Saville; Ly-Mee Yu; Hannah Swayze

Including a second primary outcome, time to recovery, change to sample size estimation, new eligibility criteria: obesity, formatting changes, blood test process.




12 (SA10) 6.0 Chris Butler; Emma Ogburn; Hannah Swayze

Addition of inhaled corticosteroid treatment arm, enrolment to additional trials, long-term follow-up, access to NHS Digital Pillar 2 test data, removal of investigators, additional trial contact with participants for up to 12 months, changes to objectives/outcomes/ time-points, removal of sampling from study

13 (NS3) 6.1 Sharon Tonner Removal of patient already taking a treatment arm medication as an exclusion


15 (SA11) 6.2 Sharon Tonner, Hannah Swayze

Inclusion of patients who lack capacity to consent, discontinuation of azithromycin arm

Lists details of all protocol amendments whenever a new version of the protocol is produced.



Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC committee, HRA (where required) or MHRA.



24 APPENDIX C: USUAL CARE ARM

1. Background and rationale COVID-19 disproportionately affects people over 50 years old with comorbidities and those over 65 years old. The disease causes considerable morbidity and mortality in this population group in particular, and is having a devastating effect on people's health, and society in the UK and internationally.(1-3, 9) So far, there are no specific treatments for COVID-19 that have been proven in rigorous clinical trials to be effective and that can be used in the community. Clinicians managing possible COVID-19 in the community will make clinical judgements about best treatment based on the clinical situation, but care is usually supportive to begin with, unless patients deteriorate and require hospital admission https://www.nice.org.uk/guidance/ng163). The National Institute for Health and Care Excellence does not recommend the immediate use of antibiotics unless there are signs of pneumonia (https://www.nice.org.uk/guidance/ng163). This Usual Care arm will follow current NHS care provision, and provides a control against which

the effect of new interventions that are added to usual care can be assessed. If a new trial

intervention plus usual care is found to be superior to usual care alone, then the usual care alone

arm will be dropped, and the intervention that is found to be most effective will become the

standard of care within the trial.

2. Changes to outcome measures None

3. Detail of intervention Participants randomised to the usual care arm will receive usual clinical care as per NHS care delivery practice.

a. Investigational Medicinal Product (IMP) description

Not applicable

b. Storage of IMP

Not applicable

4. Safety reporting Mechanisms for safety reporting are outlined in the trial protocol.

https://www.nice.org.uk/guidance/ng163

https://www.nice.org.uk/guidance/ng163



25 APPENDIX D: USUAL CARE PLUS HYDROXYCHLOROQUINE ARM (DISCONTINUED)

1. Background and rationale

a. Evidence for potential Hydroxychloroquine benefits in COVID-19

A candidate intervention for COVID-19, a drug called hydroxychloroquine, has become available following early evaluation in some studies in China.(15, 16) Hydroxychloroquine is a hydroxylated version of the drug chloroquine.(16, 17) Both agents are commonly in use as anti-malarials, and are used in a variety of auto-immune diseases. They have received significant recent interest as potential modifiers of disease activity in COVID-19. (16, 18, 19) Hydroxychloroquine is already available within the NHS on prescription for other indications, and has a generally benign safety profile.(20) Chloroquine is available to buy in the UK over the counter in some formulations and is used as antimalarial prophylaxis and treatment.

Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV.(5) Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo.(17) Chloroquine is widely distributed in the whole body, including lungs, after oral administration.(16) The EC90 value of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM in one study (15) which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration.(20) Hydroxychloroquine has been found to be effective against intracellular micro-organisms including malaria and intracellular bacteria Coxiella burnetii and Tropheryma Whipplei.(17) Both chloroquine and hydroxychloroquine have been shown to have in vitro antiviral activity against SARS coronavirus in a number of studies.(17) Most recently activity against SARSCOV2 was shown to be greater for hydroxychloroquine than chloroquine (21). Key publications that have relevance to the safety and rationale for use of hydroxychloroquine in the PRINCIPLE Trial: 1. The Mahévas study was an observational study that assessed whether hydroxychloroquine reduced the need for transfer to ICU in patients already sick enough to be hospitalised.(22) It focussed on sicker patients with hypoxic pneumonia, some requiring ITU care. It did not find a difference in transfers to ICU. So the question and population in the Mahevas study are very different compared to PRINCIPLE. Most importantly, unlike PRINCIPLE, the Mahevas study is not a randomised clinical trial. Numbers were relatively small (n=181), and it is at high risk of bias due to the observational design. Regarding safety, those receiving hydroxychloroquine were prescribed 600mg per day, whereas the dose in the PRINCIPLE trial is 400mg per day; 18% of those who received hydroxychloroquine in the Mahévas study were also on azithromycin (which can be arrhythmogenic), and this combination is not possible in PRINCIPLE because of the additive risk. Moreover, PRINCIPLE excludes several other drug combinations that could be arrhythmogenic. In the Mahevas study, eight patients (10%) who were taking hydroxychloroquine experienced electrocardiographic changes that required discontinuation of hydroxychloroquine. Critically, those in the control



group did not have ECGs done, so we don’t know if there was indeed a difference between groups, and we cannot therefore attribute the ECG changes to hydroxychloroquine. COVID-19 itself, or drug interactions, may well have been underlying reasons. The authors state, “Although hydroxychloroquine is considered safe in the context of systemic lupus erythematosus, these adverse events might be explained by the use of high dose hydroxychloroquine in patients older than 75 years with renal impairment and frequent drug interactions. We cannot rule out the possibility that these cardiac effects attributed to hydroxychloroquine were caused by COVID-19, especially given electrocardiograms were unavailable during follow-up in the control group.” 2. The Tang study was a hospital-based, randomised study and included 150 patients; randomisation was done using sealed envelopes.(23) The trial found no difference in the proportion of patients with two sequential negative swab results. Regarding safety,75 participants received hydroxychloroquine 1200 mg daily for 3 days and then 800 mg for either 2 or 3 weeks. Again, the dose used in this study was much higher that the dose being used in PRINCIPLE (initially three times, and subsequently twice as high as PRINCIPLE). However, 63% and 64% of patients in the hydroxychloroquine and control groups respectively also received other antiviral agents. In PRINCIPLE, we are not evaluating the combination of antiviral agents and hydroxychloroquine. Importantly, this study did not find evidence of cardiac arrhythmias associated with hydroxychloroquine use. The authors sate, “Events of cardiac arrhythmia, such as prolonged QT interval were not observed in our trial, possibly because of the relatively mild to moderate disease of patients investigated or the short term period of follow-up.” 3. The Mehra study published in the Lancet on 22.05.2020 reported an association between hydroxychloroquine use and cardiac events and mortality amongst patients hospitalised with COVID-19.(24) The observational study design is inherently susceptible to bias, the study data integrity has been queried given the homogeneity of the baseline characteristics, the adequacy of the adjustment for confounders cannot be assessed from the published methods, and the registries used are in a different patient population compared to PRINCIPLE. Patients were much sicker and more advanced in the illness than in PRINCIPLE. The authors themselves state that “Randomised clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents (hydroxychloroquine and chloroquine) in COVID-19 patients.” The authors also state “These data do not apply to the use of any treatment regimen used in the ambulatory, out-of-hospital setting.” This study has proved hugely controversial on social media, with a number of methodological and data integrity concerns already raised, for example: 1. There were inadequate adjustments for known and measured confounders (disease severity,

temporal effects, site effects, dose used). 2. The authors have not adhered to standard practices in the machine learning and statistics

community. They have not released their code or data. There is no data/code sharing and availability statement in the paper. The Lancet was among the many signatories on the Wellcome statement on data sharing for COVID 19 studies.

3. There was no ethics review. 4. There was no mention of the countries or hospitals that contributed to the data

source, no acknowledgments to their contributions. A request to the authors for information on the contributing centres was denied.

5. Data from Australia are not compatible with government reports (too many cases for



just five hospitals, more in-hospital deaths than had occurred in the entire country during the study period). Surgisphere (the data company) have since claimed this was an error of classification.

6. Data from Africa indicate over 40% of all COVID-19 cases and deaths in the continent occurred in Surgisphere-associated hospitals which had sophisticated electronic patient data recording, and patient monitoring able to detect and record “non-sustained [at least 6 secs] or sustained ventricular tachycardia or ventricular fibrillation”. This seems unlikely.

7. Unusually small reported variances in baseline variables, interventions and outcomes between continents

8. Mean daily doses of hydroxychloroquine that are 100 mg higher than FDA recommendations, whilst 66% of the data are from North American hospitals.

9. Implausible ratios of chloroquine to hydroxychloroquine use in some continents. 10. The tight 95% confidence intervals reported for the hazard ratios are unlikely. For instance,

for the Australian data this would need about double the numbers of recorded deaths that were reported in the paper.

This paper has now been retracted, and the data cannot be verified. 4. The Geleris study was an observational study of 1,376 consecutive COVID-19 patients at a New York hospital to determine whether hydroxychloroquine use was associated with intubation or death, as a primary composite outcome.(25) 811 (58.9%) of these patients received hydroxychloroquine. The authors excluded patients who were intubated, died, or who were transferred to another facility within 24 hours after presentation to the emergency department from the analyses. A propensity score matching model (C-statistic of 0.81) was used to ensure that groups were similar at baseline. Regarding safety, multivariable adjusted analyses with inverse probability weighting revealed no significant association between treatment with hydroxychloroquine and intubation or death (HR 1.04 (95% CI 0.82 – 1.32)). Whilst the patient population in this study is different to that of PRINCIPLE, it is interesting that the findings contrast with those of a recent Lancet study published by Mehra et al. One possible reason for the difference is that patients receiving interventions like hydroxychloroquine in the study by Mehra et al were sicker than those in the study’s control group. This may have arisen through use of crude measures to account for baseline disease severity (qSOFA score and SpO2 < 94%) in their propensity score matching model, and may also explain the big differences seen in patients requiring mechanical ventilation between controls (7.7%) and those in intervention groups (20-21.6%). 5. Boulware and colleagues conducted a Covid-19 postexposure prophylaxis, placebo controlled randomised trial of hydroxychloroquine in 821 asymptomatic patients; 11.8% of those taking hydroxychloroquine vs 14.3 of those taking placebo experienced a new illness compatible with COVID-19 (absolute difference -2.4%) but this difference was not statistically significant, indicating no evidence of benefit from the hydroxychloroquine. (26) Regarding safety, while side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), no serious adverse reactions were reported.



Earlier studies of hydroxychloroquine for COVID-19 1. Chen and colleagues conducted a randomised controlled trial to test the effectiveness of hydroxychloroquine in 30 adult patients who tested positive for COVID-19 in China.(27) Patients in the treatment group received 400mg of hydroxychloroquine for 5 days, while the control group received usual care. The result of a nasopharyngeal swab on Day 7 was used as the primary outcome. The intention- to- treat analysis revealed that the treatment group did not differ from the control group in the number of patients testing negative for COVID-19 on Day 7 (13 versus 14 patients), nor the duration of illness (all P>0.05). Regarding safety, the authors report three adverse events in the control group (one patient with abnormal liver function and anaemia, and one patient with abnormal renal function), and four adverse events in the treatment group (two patients with diarrhoea, one with lethargy, and one patient with abnormal liver function tests), which the authors argue were not linked to treatment with HCQ. One patient in the treatment group deteriorated significantly and thus HCQ was stopped on Day 4 of the treatment. This study was under-powered according to their own calculations. 2. Gautret and colleagues presented the results of an open- label, non-randomised trial with 36 patients diagnosed with COVID-19 in French hospitals.(28) Six participants were asymptomatic, 22 had upper respiratory tract infection symptoms, and eight had lower respiratory tract infection symptoms. The twenty patients in the treatment group received HCQ 200mg three times a day for 10 days. Patients declining to take part in the study and not meeting the inclusion criteria were assigned to the control group and received usual care. Six of the patients in the treatment group additionally received azithromycin to prevent bacterial superinfection. The primary outcome was SARS- CoV-2 carriage at Day 6 on nasopharyngeal swabs. Patients treated with hydroxychloroquine were significantly more likely to test negative for SARS- CoV-2 on Day 6 compared with controls (70% versus 12.5% virologically cured, p<0.001). All patients treated with hydroxychloroquine and azithromycin tested negative on Day 6. Regarding safety, the authors did not report any safety data, stating that this would follow in a subsequent publication. Aside from a lack of adverse event reporting, there are many problems with the study methodology including the non-randomized design, under-powered sample size, lack of intention-to-treat analysis, and absence of medium to long-term follow-up data. 3. Chen and colleagues conducted a randomised clinical trial of adult patients admitted to hospital with confirmed COVID-19.(7) Sixty two patients were randomly assigned to usual care (n=31) or hydroxychloroquine (200 mg BD) for five days in addition to usual care (n=31). The authors report that there were ‘significant differences’ in time to clinical recovery (TTCR) between the two groups, with TTCR defined as the return of body temperature and cough relief, maintained for more than 72 hours. They also report that all four patients who ‘progressed to severe disease’ were in the control group. The reporting of empirical data by the authors is limited and unclear. They did not include a power calculation, but presumably this study was under-powered to detect differences between groups. No medium to long-term follow-up data is presented. Regarding safety, the authors report that two mild adverse events occurred (a rash and a headache), both of which were in patients receiving hydroxychloroquine. No patients receiving usual care experienced adverse events.



In summary The large scale hospital based Recovery trial has recently announced that they found no benefit from hydroxychloroquine (as yet unpublished). No safety concerns have been reported by the Principle Trial. A post exposure prophylaxis study found no benefit from hydroxychloroquine, but also found no safety concerns. These studies address a different research question and focus on different patient populations in comparison to the Principle Trial. Evidence about early treatment of COPVID-19 in the community is urgently needed: the potential application of the findings of the PRINCIPLE Trial of community treatment is considerable, and the ‘reach’ of the study is now nation-wide. Our study population are patients in the community and our trial question is about early treatment. Outcome data from studies with sicker hospitalised patients may not apply to our study population A key, controversial observational study (Mehra et al) reported that those taking hydroxychloroquine had worse outcomes and suffered more cardiac events than those not taking hydroxychloroquine. However, major doubts have been expressed about the data integrity of this study and insufficient detail in the paper to judge the adequacy of the methods employed to adjust for the inevitable confounders in an observational study. Hydroxychloroquine is not a licensed drug for treating COVID-19. Patients doing well are therefore less likely to be prescribed this drug. When a patient is causing their clinical team more concern or their condition is deteriorating, the chances of them being prescribed hydroxychloroquine will be greater. Adjustment for potential confounders has been inadequate in the observational studies. Critically, these studies cannot adjust for the clinician’s sense of how the patient is faring over time. The Mehra study has been retracted and can’t be relied upon. The deficiencies and differences in all of these studies highlight the need for well-conducted, adequately powered randomised clinical trials, to provide definitive evidence of the safety and effectiveness of hydroxychloroquine for the early community treatment COVID-19 illness. PRINCIPLE will assess whether hydroxychloroquine is safe and effective if given earlier in the course of illness and in patients with milder symptoms not requiring hospital admission.

2. Eligibility criteria specifically related to hydroxychloroquine Inclusion criteria:

Exclusion criteria:

Pregnancy;

Breastfeeding;

Known severe hepatic impairment;

Known severe renal impairment;

Known porphyria;

Type 1 diabetes or insulin dependent Type 2 Diabetes mellitus ;

Known G6PD deficiency;

Known myasthenia gravis;

Known severe psoriasis;

Known severe neurological disorders (especially those with a history of epilepsy—may lower seizure threshold)

Previous adverse reaction to, or currently taking, hydroxychloroquine or chloroquine



Patients currently taking the following drugs: penicillamine, amiodarone, ciclosporin, digoxin: the following antimicrobials; azithromycin, clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin, ketoconazole, itraconazole, or mefloquine: the following antidepressants; amitriptyline, citalopram, desipramine, escitalopram, imipramine, doxepin, fluoxetine, wellbutrin, venlafaxine; the following antipsychotics or mood stabilizers; haloperidol, droperidol, lithium, quetiapine, thioridazine, ziprasidone: methadone: sumatriptan, zolmitriptan

Known congenital or documented QT prolongation

Known retinal disease

3. Outcome measures related to hydroxychloroquine There are no outcome measures related specifically to this usual care plus hydroxychloroquine arm

4. Detail of intervention Participants randomised to the usual care plus hydroxychloroquine arm will receive usual clinical care as per NHS guidelines, plus a course of oral hydroxychloroquine 200mg twice daily for seven days.


Hydroxychloroquine sulphate 200 milligram (mg) tablets. The tablets are for oral administration. One tablet (200mg) hydroxychloroquine to be taken twice daily for 7 days by mouth (14 tablets in total). Special instructions: Each dose should be taken with a meal or glass of milk. Antacids may reduce absorption of hydroxychloroquine so it is advised that a 4-hour interval be observed between taking hydroxychloroquine and an antacid. This is the standard therapeutic dose for its normal indication in adults which is for the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight. The Marketing Authorisation holder is Zentiva Pharma UK Limited Guildford Surrey GU1 4YS United Kingdom. Marketing authorisation number is PL 17780/0748.

b. Storage of IMP

: Stored at room temperature in locked cupboards in restricted access rooms in the Nuffield Department of Primary Care Health Sciences; in locked cupboards in restricted access rooms in GP Practices; in Pharmacies. For hydroxychloroquine, GP practices can order a supply of trial medication from Public Health England using the existing ImmForm process. GPs will be provided with an envelope by the trial team which will be labelled appropriately for trial medication, and they will add the patient’s details to this label. This pack, containing instructions on using the medication will be provided to the patient or their representative.



c. SmPC precautions and concomitant medication

Hydroxychloroquine: Hydroxychloroquine will be used for short-term use (7 days) in this trial. The SmPC and precautions listed below focus on longer term chronic use.

i. Precautions

Hydroxychloroquine might lower blood sugar levels in some people. If participants develop these symptoms, they will be advised in the Patient Information documents to eat something sweet and seek clinical advice if the symptoms continue. Hydroxychloroquine occasionally causes blurred vision, which typically resolves once the medication is stopped. Participants will be advised via the Participant Information documents that if they develop any problems with vision, they should stop taking the medication immediately, seek clinical advice, and not drive or operate any heavy machinery.

ii. Concomitant medication

Hydroxychloroquine sulfate has been reported to increase plasma digoxin levels. Serum digoxin levels should be closely monitored in participants receiving concomitant treatment. Hydroxychloroquine sulfate may also be subject to several of the known interactions of chloroquine even though specific reports have not appeared. These include: potentiation of its direct blocking action at the neuromuscular junction by aminoglycoside antibiotics; inhibition of its metabolism by cimetidine which may increase plasma concentration of the antimalarial; antagonism of effect of neostigmine and pyridostigmine; reduction of the antibody response to primary immunisation with intradermal human diploid-cell rabies vaccine. As with chloroquine, antacids may reduce absorption of hydroxychloroquine so it is advised that a four hour interval be observed between hydroxychloroquine and antacid dosaging. As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required. Halofantrine prolongs the QT interval and should not be administered with other drugs that have the potential to induce cardiac arrhythmias, including hydroxychloroquine. Also, there may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine is used concomitantly with other arrhythmogenic drugs, such as amiodarone and moxifloxacin. An increased plasma ciclosporin level was reported when ciclosporin and hydroxychloroquine were co-administered. Hydroxychloroquine can lower the convulsive threshold. Co-administration of hydroxychloroquine with other antimalarials known to lower the convulsion threshold (e.g. mefloquine) may increase the risk of convulsions. Also, the activity of anti-epileptic drugs might be impaired if co-administered with hydroxychloroquine. In a single-dose interaction study, chloroquine has been reported to reduce the bioavailability of praziquantel. It is not known if there is a similar effect when hydroxychloroquine and praziquantel are co-administered. Per extrapolation, due to the similarities in structure and pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect may be expected for hydroxychloroquine.



There is a theoretical risk of inhibition of intra-cellular α-galactosidase activity when hydroxychloroquine is co-administered with agalsidase.

iii. Pregnancy and Breastfeeding

A moderate amount of data on pregnant women (between 300 – 1000 pregnancy outcomes), including prospective studies in long-term use with large exposure, have not observed a significant increased risk of congenital malformations or poor pregnancy outcomes. Hydroxychloroquine crosses the placenta. Only limited non-clinical data are available for hydroxychloroquine, data on chloroquine have shown developmental toxicity at high supratherapeutic doses and a potential risk of genotoxicity in some test systems. Therefore, hydroxychloroquine sulfate should be avoided in pregnancy except when, in the judgement of the physician, the individual potential benefits outweigh the potential hazards. Careful consideration should be given to using hydroxychloroquine during lactation, since it has been shown to be excreted in small amounts in human breast milk, and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines. Pregnancy and breastfeeding are exclusion criteria for the hydroxychloroquine arm of the PRINCIPLE trial.

5. Safety reporting Hydroxychloroquine: has a well-documented safety profile and is a commonly used medication in a primary care setting (see above). Common symptoms of hydroxychloroquine include abdominal pain; appetite decreased; diarrhoea; emotional lability; headache; nausea; skin reactions; vision disorders; and vomiting. Mechanisms for safety reporting are outlined in the trial protocol.

We will call all participants randomised to hydroxychloroquine on day 7 to ask about

cardiovascular AEs. Our team of clinicians will review any AEs relating to cardiovascular symptoms

from the day 7 call, and assess whether these may be related to hydroxychloroquine. If AEs are

thought to be related and it’s deemed necessary by the assessing clinician, the participant’s GP

will be contacted to arrange a face-to-face visit for further clinical evaluation.



26 APPENDIX E: USUAL CARE PLUS AZITHROMYCIN ARM (DISCONTINUED)


a. Evidence for potential Azithromycin benefits in COVID-19

Atypical macrolides, especially Azithromycin, have activities that may be beneficial in the

treatment of COVID-19 patients, and especially those in the at-risk or age range of the PRINCIPLE

trial.

Firstly, Azithromycin appears to have some anti-viral mechanisms. In COVID-19, Azithromycin

appears to inhibit viral replication and therefore reduces shedding. In the small open

observational trial of Gautret et al the addition of azithromycin to hydroxychloroquine (HCQ) (at

200 tds for 10 days) in 6 of the 14 HCQ subjects of the total 36 COVID-19 patients in the study

significantly reduced viral shedding at 3 days to 15% (one subject) versus 70% in the HCQ arm and

95% in the indirect control arm, with no shedding at 6 days in the combination arm versus 50%

and 90% respectively.(28) Azithromycin was also used in some Chinese observational and

interventional studies.

Azithromycin has also been shown to be active in vitro against Zika and Ebola viruses,(29-31) and

to prevent severe respiratory tract infections when administrated to patients suffering viral

infection.(32) Inhibition of viral infections by azithromycin may be linked to its suppressive effect

on the production of viral interferon.(33) Longer term administration of low dose azithromycin in

COPD has been shown to suppress proinflammatory cytokine production, potentiate macrophage

phagocytosis and anti-inflammatory cytokine expression.(34-36) Azithromycin use is also

associated with a decrease in the expression of human HLA (human leukocyte antigen) complex

molecules in the respiratory tract, including HLA-A, HLA-B, HLA-DPA1, HLA-DRA, HLA-DRB4.(37)

b. Importance of treating CAP or CAP risk in the elderly or immuno-compromised

An important secondary pathway to severe illness and death with COVID-19 may be secondary

infection and sepsis in the immune-compromised state, especially secondary community or

hospital acquired pneumonia. Older people are more susceptible to pneumonia because of

comorbidities, a weakened immune system and are therefore more likely to die.(38) The onset of

pneumonia in the elderly can often be rapid, and for severe pneumonia, the prognosis is poor: as

many as one in five will die.(38) Severe pneumonia is more prevalent the older you are and in

those with more serious underlying diseases.(39) The leading cause of death is respiratory

insufficiency. Death has been shown to increase in those not responding to initial antimicrobials,

and consequently, the initial selection of the agent is important.

Common causative organisms in the elderly admitted to the hospital with pneumonia include

Haemophilus influenza, Staphylococcus aureus, Streptococcus pneumoniae, and Mycoplasma

pneumoniae. In severe pneumonia, S. aureus, Klebsiella pneumoniae, and Pseudomonas

aeruginosa have been identified as common causative organisms. Older patients often have

polymicrobial infections, which may be a factor in non-responders. Assessment of 12,945 US



Medicare inpatients over 65 with pneumonia found that initial treatment with a second-

generation cephalosporin plus macrolide ([HR, 0.71; 95% CI, 0.52-0.96), a non-pseudomonas

third-generation cephalosporin plus a macrolide (HR, 0.74; 0.60-0.92), or a fluoroquinolone alone

(HR, 0.64; 0.43-0.94) was associated with lower 30-day mortality.(40)

For CAP management NICE guidance currently recommends Amoxycillin 500mg tds combined with Clarithromycin 500mg bd for 5 days or, in penicillin sensitive, Clarithromycin 500mg bd for 5 days or Doxycycline 200mg stat then 100mg daily for the next 4 days. They also recommend starting therapy within 4 hours. The identification of the early stages of pneumonia in older patients can prove challenging since traditional symptoms and signs, including fever, may be lacking. Azithromycin will have at least as broad a spectrum of action as clarithromycin in terms of

bacterial infections and the additional potential anti-viral activity which has not been observed

for other macrolides like Clarithromycin. It will also cover atypical organisms.

2 Changes to outcome measures The addition of this usual care plus azithromycin arm will not require any changes to outcome measures

3 Eligibility criteria specifically related to azithromycin Inclusion criteria: No changes

Exclusion criteria:

Pregnancy

Breastfeeding

Known severe hepatic impairment;

Known severe renal impairment;

Known myasthenia gravis;

Previous adverse reaction to, or currently taking, azithromycin or other macrolides or

ketolides

Patients taking the following drugs: hydroxychloroquine or chloroquine, sotalol, amiodarone, ciclosporin, digoxin, bromocriptine, cabergoline, ergotamine, ergometrine, methysergide or any ergot derivatives.

Already taking antibiotics for an acute condition

Known congenital or documented QT prolongation

Known allergy to soya or peanut due to the risk of hypersensitivity reactions

4 Detail of intervention Participants randomised to the usual care plus azithromycin arm will receive usual clinical care as per NHS guidelines, plus a course of oral azithromycin 500mg daily for three days. We will use the IMP distribution methods described in the protocol to deliver IMP to participants.




Azithromycin 250mg capsules. Participants in this arm will take 500 mg (two capsules) once daily for 3 days. The capsules are for oral administration. Special instructions: Azithromycin must be taken at least 1 hour before or 2 hours after antacids as this affects overall bioavailability. Azithromycin must be taken at least 1 hour before or 2 hours after food. The marketing authorisation holder is: Teva UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, UK. Marketing authorisation number: PL 00289/1570

b. Storage of IMP

Azithromycin: Stored at room temperature in locked cupboards in restricted access rooms in the Nuffield Department of Primary Care Health Sciences; in locked cupboards in restricted access rooms in GP Practices; in Pharmacies.


i. Precautions

Azithromycin is a commonly prescribed antibiotic with an established safety profile. The SmPC advises caution using azithromycin in the following conditions: Elderly people with proarrhythmic conditions due to the risk of developing cardiac arrhythmia and torsades de pointes including patients with congenital or documented QT prolongation; receiving treatment with other active substances known to prolong QT interval such as anti-arrhythmics (e.g. amiodarone and sotalol), cisapride, and fluoroquinolones such as moxifloxacin and levofloxacin; known hypokalaemia and hypomagnesaemia; significant hepatic or renal impairment; patients with neurological or psychiatric disorders; myasthenia gravis. Azithromycin as other with the use of nearly all antibacterial agents, alters the normal flora of the colon leading to overgrowth of Clostridium difficile which can lead to Clostridium difficile associated diarrhoea.

ii. Concomitant medications

Effects of other medicinal products on azithromycin: Antacids

In a pharmacokinetic study investigating the effects of simultaneous administration of antacids and azithromycin, no effect on overall bioavailability was seen, although the peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the medicinal products should not be taken simultaneously. Azithromycin must be taken at least 1 hour before or 2 hours after the antacids.

Co-administration of azithromycin prolonged-release granules for oral suspension with a single 20 ml dose of co-magaldrox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.

Co-administration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.



Fluconazole

Co-administration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Nelfinavir

Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.

Rifabutin

Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either medicinal product.

Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established.

Terfenadine

Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however, there was no specific evidence that such an interaction had occurred.

Cimetidine

In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Effect of azithromycin on other medicinal products: Ergotamine derivatives

Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended.

Digoxin and colchicine (P-gp substrates)

Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.

Coumarin-Type Oral Anticoagulants

In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15-mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of



monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Cyclosporin

In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Theophylline

There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers. As interactions of other macrolides with theophylline have been reported, alertness to signs that indicate a rise in theophylline levels is advised.

Trimethoprim/sulfamethoxazole

Coadministration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 had no significant effect on peak concentrations total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.

Zidovudine

Single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

Astemizole, alfentanil

There are no known data on interactions with astemizole or alfentanil. Caution is advised in the co-administration of these medicines with azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolid antibiotic erythromycin.

Atorvastatin

Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay).

However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.

Carbamazepine



In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.

Cisapride

Cisapride is metabolized in the liver by the enzyme CYP 3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsades de pointes.

Cetirizine

In healthy volunteers, coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Didanosins (Dideoxyinosine)

Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

Efavirenz

Coadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Indinavir

Coadministration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.

Methylprednisolone

In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam

In healthy volunteers, coadministration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.

Sildenafil

In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.

Triazolam

In 14 healthy volunteers, coadministration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.



iii. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of azithromycin in pregnant women. In reproduction toxicity studies in animals azithromycin was shown to pass the placenta, but no teratogenic effects were observed. The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore azithromycin should only be used during pregnancy if the benefit outweighs the risk.

5 Safety reporting Mechanisms for safety reporting are outlined in the protocol. In brief, we will collect symptoms

and side effects of azithromycin from symptom diaries and participant telephone calls.

Common symptoms of azithromycin include diarrhoea, abdominal pain, nausea and flatulence. It

may also cause headache, dizziness, insomnia, altered taste, pins and needles, changes in vision

or hearing, rash, itching, joint pains or fatigue.



26 APPENDIX F: USUAL CARE PLUS DOXYCYCLINE ARM


a. Evidence for potential doxycycline benefits in COVID-19

Doxycycline may be beneficial in the treatment of COVID-19 patients, and especially those in the

at-risk or age range of the PRINCIPLE trial.

The rationale for testing doxycycline is based on three reasons:

Firstly, doxycycline may have direct antiviral activity against SARS-CoV-2 based on computer

modelling. Analysing all the proteins encoded by SARS-CoV-2 genes and then predicting potential

targets by performing target-based virtual ligand screening, doxycycline ranked in the group of

compounds with the highest binding affinity to 3CLpro (3-chymotrypsin-like protease). 3CLpro is

the main protease in SARS- CoV-2 which is critical in the life-cycle of the virus (41).

Secondly, doxycycline has known anti-inflammatory effects in various human diseases by

inhibiting mitogen-activated protein kinase (MAPK) and SMAD pathways (42), as well as potent

antioxidant properties(43). Doxycycline reduces the hyperinflammation associated with severe

COVID-19 by antagonising metalloproteinases such as MMP9 that are linked with lung injury,

including SARS and ARDS(44).

Lastly, from extensive experience in other infectious diseases, doxycycline has broad

antimicrobial activity and is efficacious against a broad spectrum of bacteria including atypical

bacteria and other pathogens including intracellular plasmodia, chlamydia, rickettsia, and RNA

viruses like Dengue fever and chikungunya.

b. Importance of treating CAP or CAP risk in the elderly or immuno-compromised

An important secondary pathway to severe illness and death with COVID-19 may be secondary

infection and sepsis in the immune-compromised state, especially secondary community or

hospital acquired pneumonia. Older people are more susceptible to pneumonia because of

comorbidities, a weakened immune system and are therefore more likely to die.(38) The onset of

pneumonia in the elderly can often be rapid, and for severe pneumonia, the prognosis is poor: as

many as one in five will die.(38) Severe pneumonia is more prevalent the older you are and in

those with more serious underlying diseases.(39) The leading cause of death is respiratory

insufficiency. Death has been shown to increase in those not responding to initial antimicrobials,

and consequently, the initial selection of the agent is important. Common causative organisms in

the elderly admitted to the hospital with pneumonia include Haemophilus influenza,

Staphylococcus aureus, Streptococcus pneumoniae and less commonly, atypical organisms, such

as Mycoplasma pneumoniae and Klebsiella pneumoniae. All these organisms fall under

doxycycline’s antimicrobial spectrum.

We are aware that currently NICE, in their COVID-19 rapid guideline, advocates that clinicians

offer oral doxycycline for treatment of suspected pneumonia in people who can or wish to be



treated in the community if: the likely cause is bacterial or; it is unclear whether the cause is

bacterial or viral and symptoms are more concerning or; they are at high risk of complications

(older or frail patients, pre-existing comorbidity or have a history of severe illness following

previous lung infection).(45) Doxycycline will have at least as broad a spectrum of action as

azithromycin in terms of bacterial infections with the potential anti-viral and anti-inflammatory

effects.

Doxycycline for acute cough and community acquired pneumonia is recommended in the British

National Formulary at a dose of Doxycycline 200mg stat then 100mg daily for the next 4 days.

However, its use in COVID-19 is not proven and therefore important to address in this trial. Given

the potential anti-inflammatory properties of doxycycline, we will use a slightly extended 7 day

course.

2. Changes to outcome measures The addition of this usual care plus doxycycline arm will not require any changes to outcome measures

3. Eligibility criteria specifically related to doxycycline Inclusion criteria: No changes

Exclusion criteria:

Pregnancy

Breastfeeding

Myasthenia gravis

Systemic lupus erythematosus

Previous adverse reaction to, or currently taking, doxycycline or other tetracyclines

Sucrose intolerance (i.e. rare hereditary problems of fructose intolerance, glucose

galactose malabsorption or sucrose-isomaltase insufficiency)

Already taking antibiotics for an acute condition

Patients taking the following drugs: ciclosporin, retinoids (acitretin, alitretinoin, isotretinoin, tretinoin), methotrexate, ergotamine, methoxyflurane, lithium.

4. Detail of intervention Participants randomised to the usual care plus doxycycline arm will receive usual clinical care as per NHS guidelines, plus a course of oral doxycycline for 7 days. We will use the IMP distribution methods described in the protocol to deliver IMP to participants.


Doxycycline 100mg capsules. Participants in this arm will take 200mg on the first day (as a single dose or in divided doses with a twelve hour interval) followed by 100mg a day for 6 days (7 day course in total). The capsules are for oral administration.



Special instructions: Capsules should be swallowed whole with plenty of fluid, while sitting or standing. Capsules should be taken during meals, well before going to bed. Due to the risk of photosensitivity, patients should be advised to avoid exposure to sunlight or sun lamps. The marketing authorisation holder is: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS Marketing authorisation number: PL 0142/0407

b. Storage of IMP

Doxycycline: Stored at room temperature in locked cupboards in restricted access rooms in the Nuffield Department of Primary Care Health Sciences; in locked cupboards in restricted access rooms in GP Practices; in Pharmacies.


i. Precautions

Doxycycline is a commonly prescribed antibiotic with an established safety profile. The SmPC states that in elderly patients “doxycycline may be prescribed in the usual dose with no special precautions. No dosage adjustment is necessary in the presence of renal impairment”.

ii. Concomitant medications

Warfarin There have been reports of prolonged prothrombin time in patients taking warfarin and doxycycline. Tetracyclines depress plasma prothrombin activity and reduced dosage of concomitant anti-coagulants may be necessary

5. Safety reporting Mechanisms for safety reporting are outlined in the protocol. In brief, we will collect symptoms

and side effects from symptom diaries and participant telephone calls.

Common side effects of doxycycline include: Angioedema; diarrhoea; headache; Henoch-

Schönlein purpura; hypersensitivity; nausea/vomiting; pericarditis; skin and photosensitivity

reaction; dyspnoea; hypotension; peripheral oedema; tachycardia.



26 APPENDIX G: USUAL CARE PLUS INHALED CORTICOSTEROID (ICS) ARM


a. Evidence for potential benefits of inhaled corticosteroids in COVID-19 illness

Inhaled corticosteroids (ICS) are a commonly prescribed class of medication throughout the world. They are reasonably cheap and have been used widely for the last 60 years. The inhaled action and type2 pneumocyte target of COVID make ICS a potential therapeutic agent in COVID-191. They have been shown to be very effective in improving asthma and COPD care over the long term, where the recommendation is that most, if not all, patients with asthma should be prescribed an inhaled corticosteroid2,3 and up to 90% of patients with COPD in the UK are prescribed ICS4. The rationale of ICS is to reduce the inflammatory process that underlies exacerbations, which can be triggered by viruses in asthma and COPD. Systemic corticosteroids have been found to be effective at reducing mortality amongst hospitalised patients with COVID-19 [46, 47], but it is not known whether pre-hospital treatment with ICS is also beneficial. Further evidence is as described below: Evidence from the ARDS literature ICS in patients at risk of acute respiratory distress syndrome (ARDS) have been shown to improve physiology and reduce inflammatory markers5. In patients admitted to hospital at risk of ARDS or acute lung injury, there was an almost 50% reduction of ARDS in patients that were using ICS pre-admission, even controlling for covariates such as age, gender and chronic respiratory disease6. Moreover, this ICS effect can also be seen to improve pulmonary physiology7. Potential mechanism of efficacy Recently published in vitro data suggest a role for ICS inhibition of coronavirus replication in infected epithelial cells8, whilst there is an indication that there is accelerated hyperinflammation at the onset of SARS-CoV-2 infection9, which potentially can be modified by anti-inflammatory therapy. This suggests a plausible mechanism for ICS efficacy against COVID-19 in which ICS has a dual role: firstly, toning down the inflammatory “runaway train” (ARDS-like) response affecting a minority of COVID-19 patients; and secondly, inhibiting viral replication. It has long been known that the ICS effect on epithelial cells is as a direct consequence of gene transcription10, and investigation of gene expression of ACE2 and TMPRSS2 in the sputum of asthmatic patients has very recently demonstrated lower expression of these key receptors in the presence of ICS11. Furthermore, ICS attenuates expression of the ACE2 receptor in human and murine in vitro and in vivo models12. This is of relevance as the SARS-CoV-2 mechanism of action is upon direct action of the ACE2 receptor, a receptor highly expressed on epithelial cells in the oral mucosa and type 2 alveolar cells and the serine protease TMPRSS2 for SARS-CoV-2 spike protein priming13,14. Furthermore, there is experimental evidence that inhaled corticosteroids inhibit coronavirus replication in vitro15,16. SARS-CoV-2 binds to cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 is highly expressed on epithelial cells in the oral mucosa and type 2 alveolar epithelial cells. The use of inhaled corticosteroids as a therapy suggests it would target the cells of interest. Furthermore, the primary action of the inhaled steroids is on the type 2 pneumocytes where viral replication is going to be at its most, where we know that ACE2 receptor expression is high.



2. Changes to outcome measures The addition of this arm will not require any changes to outcome measures.

3. Eligibility criteria specifically related to ICS

Inclusion criteria: No changes

Exclusion criteria:

A known allergy to inhaled corticosteroids

Any known contraindication to inhaled corticosteroids (as per SmPC, patients with rare

hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-

galactose malabsorption should not take this medicine. Lactose, the excipient in the

product, contains small amounts of milk proteins and can therefore cause allergic

reactions).

Patient currently prescribed inhaled or systemic corticosteroids

Unable to administer inhaler

4. Detail of intervention Participants randomised to the usual care plus ICS arm will receive usual clinical care as per NHS guidelines, plus inhaled corticosteroids for 14 days. We will use the IMP distribution methods described in the protocol to deliver IMP to participants.


The IMP is the inhaled corticosteroid budesonide (dose 400mcg, Pulmicort turbohaler®). Inhaled budesonide comes in a polyethylene container consisting of a white cover screwed onto a brown bottom plate. Inside this is the inhaler with its main parts: a mouthpiece, a dosing mechanism and a substance store. The device will have 50 actuations of 400mcg/actuation. This product has marketing authorisation in the UK (PL 17901/0164) and is manufactured by AstraZeneca UK Ltd, 600 Capability Green, Luton, LU1 3LU, UK. This IMP will be taken as 2 puffs twice a day for 14 days.

b. Storage of IMP

Stored at room temperature in locked cupboards in restricted access rooms in the Nuffield Department of Primary Care Health Sciences; in locked cupboards in restricted access rooms in GP practices; in Pharmacies


iii. Precautions

Budesonide is a commonly prescribed inhaled steroid with an established safety profile.

iv. Concomitant medications

Largely, there is no restriction to concomitant medications using inhaled budesonide. The SmPC states that concomitant treatment with ketoconazole, HIV protease inhibitors or other



potent CYP3A inhibitors may increase systemic budesonide levels, but that this is of little clinical significance for a short term treatment of 2 weeks, which is the duration of IMP use in the trial.

5. Safety reporting Mechanisms for safety reporting are outlined in the protocol. In brief, we will collect symptoms and side effects from symptom diaries and participant telephone calls.

Common and/or potential side effects from IMP include:

Cough immediately after inhaling

Mouth and throat pain

Hoarse voice

Oral candidiasis (thrush)

These are all reversible upon ceasing IMP



27. Supplementary Material

A. Abbreviations

AE Adverse event

AR Adverse reaction

CI Chief Investigator

CRF Case Report Form

CT Clinical Trials

CTA Clinical Trials Authorisation

CTRG Clinical Trials and Research Governance

DMSC Data Monitoring Committee / Data Monitoring and Safety Committee

DSUR Development Safety Update Report

GCP Good Clinical Practice

GP General Practitioner

HRA Health Research Authority

HCP Healthcare professional

IB Investigators Brochure

ICF Informed Consent Form

ICH International Conference on Harmonisation

IMP Investigational Medicinal Product

MHRA Medicines and Healthcare products Regulatory Agency

NHS National Health Service

NIHR National Institute of Health Research

RES Research Ethics Service

PHE Public Health England

PI Principal Investigator

PIL Participant/ Patient Information Leaflet

R&D NHS Trust Research and Development Department

RCGP RSC Royal College of General Practitioners Research Surveillance Centre

REC Research Ethics Committee

RSI Reference Safety Information

SAE Serious Adverse Event

SAR Serious Adverse Reaction

SDV Source Data Verification

SMPC Summary of Medicinal Product Characteristics

SOP Standard Operating Procedure

TSC Trial Steering Committee

SUSAR Suspected Unexpected Serious Adverse Reactions

TMF Trial Master File



B. Key Trial Contacts

Chief Investigator Professor Chris Butler Nuffield Department of Primary Care Health Sciences Gibson Building Radcliffe Observatory Quarter Woodstock Road Oxford OX2 6GG [email protected]

Sponsor Joint Research Office 1st floor, Boundary Brook House Churchill Drive, Headington Oxford OX3 7GB [email protected] Tel: +44 (0)1865572224 Fax: +44 (0)1865572228

Funder(s) UKRI/NIHR

Clinical Trials Unit Primary Care Clinical Trials Unit, Nuffield Department of Primary Care Health Sciences Radcliffe Observatory Quarter Woodstock Road Oxford OX2 6GG [email protected] 01865 289296

Statistician Ben Saville, Berry Consultants, Austin, Texas, USA, And Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. Dr Ly-Mee Yu Primary Care Clinical Trials Unit, Nuffield Department of Primary Care Health Sciences Radcliffe Observatory Quarter Woodstock Road Oxford OX2 6GG

Committees DMSC Chair: Prof. Deborah Ashby Chair in Medical Statistics and Clinical Trials Director of the School of Public Health Imperial College London Faculty of Medicine, School of Public Health, 153 Medical School St Mary's Campus Imperial College London [email protected]







(0)20 7594 8704 DMSC Members: Prof Simon Gates Cancer Research Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences University of Birmingham Edgbaston Birmingham B15 2TT [email protected] Prof Gordon Taylor College House, University of Exeter, St Luke's Campus, Heavitree Road, Exeter, EX1 2LU, UK [email protected] Prof Nick Francis Primary Care and Population Science, University of Southampton, Southampton, UK. [email protected]

TSC Chair Prof Paul Little, Primary Care and Population Science, University of Southampton, Southampton, UK. [email protected] TSC Members Prof Philip Hannaford, NHS Professor of Primary Care University of Aberdeen, Aberdeen, UK [email protected] Prof Matt Sydes, Professor of Clinical Trials & Methodology, MRC Clinical Trials Unit, University College of London, London, UK [email protected] PPI representatives Ms Carol Green Mr Tim Mustill








C. Objectives and Outcome Measures

Objectives Outcome Measures Timepoint (s)

Primary

To assess the effectiveness of trial treatments in reducing 1) Time to recovery, for patients aged ≥50 years with comorbidity, and aged ≥65 with or without comorbidity and possible COVID-19 during a time of prevalent COVID-19 disease, and 2) Hospitalisation and/or death.

1) Time to recovery, defined as the first instance that a participant reports feeling recovered from possible COVID-19, and 2) Hospitalisation and/or death

Within 28 days of randomisation Patient report, Study Partner report, medical records, Daily online symptom scores

Secondary

To explore whether trial treatment reduces

1) Patient-reported illness severity

2) Duration of severe symptoms and symptom recurrence

3) Contacts with the health services

4) Consumption of antibiotics

5) Hospital assessment without admission

6) Oxygen administration

7) Intensive Care Unit admission

8) Mechanical ventilation

9) Duration of hospital admission

10) Negative effects on well being

11) New infections in household

12) To determine if effects are specific

1-2. Patient reports daily and monthly (after 28 days) symptoms.

3. Contacts with health services reported by patients and/or captured by reports of patients’ medical records if the practice is a member of the RCGP RSC network

4. Bi-weekly reports from participants’ primary care medical records

5-9. Patient report/carer report/medical record in primary and secondary care

9

10. WHO-5 Well Being Index

11. Reports of new infections in the household (from daily questionnaire)

Daily online symptom scores.

Telephone call or text on days 2, 7, 14 and 28 and once a month for 12 months if data is not obtained through the online diary.

GP notes review if available through Oxford RCGP RSC network; otherwise, other sources of routinely collected data after 28 days. Medical notes review for up to 10 years.

HES/ONS/EMIS/Medical record data linkage after 28 days if patients have been assessed in hospital

Swab result from medical records, the supporting laboratory



to those with a positive test for SARS-CoV-2

12. Swab test results will indicate an “Intention to Treat Infected” group within the overall cohort for sub analysis. Blood test results on recovery (optional) for evidence of historic COVID-19

and/or convalescent blood test result for evidence of historic COVID-19 WHO 5 Well Being Index at baseline, day 14, and day 28 and monthly for up to 12 months, either via online diary or telephone

Qualitative sub-study

1. To explore patients’ experiences of consulting, being tested and taking (trial) medication for possible COVID-19.

2. To explore healthcare professionals’ views of taking part in research during pandemics.

1. Telephone interviews with patients.

2. Telephone interviews with healthcare professionals.

1. After 28 days.

2. Once practice has completed recruitment.

Intervention(s) All trial interventions are detailed in the Appendices. Further interventions may be added or replaced during the course of the trial, subject to suitable interventions becoming available and all necessary approvals being obtained.

Comparator In the first instance, this will be a two-arm trial, with the intervention arm being usual care plus a trial drug and the comparator being usual care. There will be no placebo control in this study. Additional arms may be added as the trial progresses. These will be detailed in the Appendices. If an intervention arm is shown to be superior, then this will become the new standard of care. However, the primary analysis of subsequent interventions will correspond to the comparison versus the original Usual Care arm.



D. Adverse Events

Definitions

Adverse Event (AE) Any untoward medical occurrence in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product.

Adverse Reaction (AR)

An untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant.

The phrase "response to an investigational medicinal product" means that a causal relationship between a trial medication and an AE is at least a reasonable possibility, i.e. the relationship cannot be ruled out.

All cases judged by either the reporting medically qualified professional or the Sponsor as having a reasonable suspected causal relationship to the trial medication qualify as adverse reactions.

Serious Adverse Event (SAE)

A serious adverse event is any untoward medical occurrence that:

results in death

is life-threatening

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability/incapacity

consists of a congenital anomaly or birth defect*.

Other ‘important medical events’ may also be considered a serious adverse event when, based upon appropriate medical judgement, the event may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed above.

NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

*NOTE: Pregnancy is not, in itself an SAE. In the event that a participant or his/her partner becomes pregnant whilst taking part in a clinical trial or during a stage where the foetus could have been exposed to the medicinal product (in the case of the active substance or one of its metabolites having a long half-life) the pregnancy should be followed up by the investigator until delivery for congenital abnormality or birth defect, at which point it would fall within the definition of “serious”.



Serious Adverse Reaction (SAR)

An adverse event that is both serious and, in the opinion of the reporting Investigator, believed with reasonable probability to be due to one of the trial treatments, based on the information provided.

Suspected Unexpected Serious Adverse Reaction (SUSAR)

A serious adverse reaction, the nature and severity of which is not consistent with the Reference Safety Information for the medicinal product in question set out:

in the case of a product with a marketing authorisation, in the approved summary of product characteristics (SmPC) for that product

in the case of any other investigational medicinal product, in the approved investigator’s brochure (IB) relating to the trial in question.

NB: To avoid confusion or misunderstanding the difference between the terms “serious” and “severe”, the following note of clarification is provided: “Severe” is often used to describe intensity of a specific event, which may be of relatively minor medical significance. “Seriousness”

E. Data Recording and Record Keeping

The data will be entered into the CRFs in an electronic format by the participant, Trial Partner or trial team (using OpenClinica™ database via Sentry). OpenClinica™ is stored on a secure server – data will be entered in a web browser and then transferred to the OpenClinica Database by encrypted (Https) transfer. OpenClinica™ meets FDA part 11B standards. This includes safety data, laboratory data and outcome data. Safety data will also be collected through electronic diaries which are stored on a secure server. Sentry is an online secure data entry system developed in-house at PC-CTU and hosted at Oxford. It is designed to collect sensitive data, such as participant and Trial Partner contact details, and securely retain them separate form a trial's clinical data. Sentry can also act as a central participant portal to manage online eligibility, eConsent and ePRO - acting as an intermediary between the participant and the clinical databases. Sentry is accessed via a secure HTTPS connection and all stored sensitive data is encrypted at rest to AES-256 standards. Participant and Trial Partner data will be kept and stored securely for as long as it’s required by the study and reviewed on annual basis.

F. Qualitative Sub-study

With consent, participants will be contacted for a telephone interview within three months after they complete their day 28 follow up. The researcher will provide study information over the telephone and the Interview Patient PIS, and ICF will be available on the study website and emailed to participants if requested.



Once a practice has completed patient recruitment and one of their patients has been interviewed, we may ask 1-2 healthcare professionals who would be willing to share their experiences of taking part in the trial. Healthcare professionals will include clinicians and non-clinicians with the main criteria for inclusion in interviews being that HCP participants should have carried out trial activities in their practice. Potential HCP participants will be contacted in person or by email by the practice contact. They will be provided with the Interview HCP Invitation Email, Interview HCP PIS and Interview HCP ICF by email. Patients recruited to both the intervention and usual care arms will be purposively sampled across the recruiting period with approximately 15-20 patients in each arm (30-40 interviews in total). We will seek to obtain maximum variation in age and symptom severity (as reported in daily diary at baseline). When the research team receives responses from HCPs, they will collect basic demographics to purposively select participants based on practice location, practice size, practice patient recruitment and job role. We aim to complete 20-25 interviews with HCPs. All participants will only be required to take part in a single interview. Patient participant interviews will follow a semi-structured topic guide (Interview Patient Topic Guide) and ask about reasons for consulting and illness perceptions prior to the consultation, experiences of the consultation, the COVID-19 testing process (if applicable, and result if the participant has been notified) and medication adherence. The topic guide will be informed by the Common Sense Model which describes how people perceive and cope with symptoms of illness. HCP interviews will follow the Interview HCP Topic Guide and will ask about experiences of carrying out trial activities, recruiting patients and the work required to set up a clinical trial during a pandemic. Interviews with patient participants are expected to last approximately 30-45 minutes and interviews with HCPs are expected to last 15-30 minutes. Data Collection: Each interview will be audio-recorded with the participant’s permission. Recordings will allow verbatim transcription of interviews. Transcription will be completed by an independent transcription company. Once transcribed and transcripts are checked, audio-recordings will be deleted. Transcripts will be labelled with a unique participant number and will omit any identifiable data either identifying the participant or their general practice.

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